**8. Economic impact**

recent paper, focused on the impact on bone healing and implant osteointegration, reported

Another study on a rat model of acutely infected osteosynthesis did provide evidence that vancomycin-loaded DAC®-coated plates and screws not only are associated with a significant reduction of infection but also protect from the occurrence of septic nonunion, compared to uncoated implants [58]. This study is the very first demonstration that bone healing in a contaminated fracture can be improved by using an osteosynthesis coated with a fast-resorbable,

The DAC® hydrogel received the CE mark at the end of year 2013. The available kit (www. coatingdac.com or www.dac-coating.com) is composed of a prefilled syringe, containing 300 mg sterile DAC® powder, that is filled at surgery with a solution of 5 mL sterile water for injection, eventually mixed with the desired antibiotic(s); this allows to obtain, in approximately 3–5 min, the antibiotic-loaded hydrogel, at a DAC® concentration of 6% (w/v) and at an antibiotic concentration usually ranging from 20 mg/mL to 50 mg/mL, depending on the surgeon's choice. The surgeons can choose the antibiotic from among a list of antibacterials previously tested as being compatible with the hydrogel (Novagenit SRL, data on file). A few minutes after reconstitution, the hydrogel can be directly spread onto the implant, which is then inserted into the body in the usual way. If necessary, once reconstituted, the hydrogel

Two large multicenter, randomized, prospective clinical trials were undertaken in Europe, within the 7th European Framework Programme (project # 277988), funded by the European Commission. In a first trial, a total of 380 patients, scheduled to undergo primary (n = 270) or revision (n = 110) total hip (N = 298) or knee (N = 82) joint replacement with cementless or hybrid (partially cemented) implants were included [59, 60]. The patients were randomly assigned, in six European orthopedic centers, to receive an implant either with the DAC® coating, intraoperatively loaded with antibiotics (treatment group), or without the coating (control group). Pre- and postoperative assessment of clinical scores, wound healing, laboratory tests and X-ray exams were performed at fixed time intervals. Overall, 373 patients were available at a mean follow-up of 14.5 ± 5.5 months (range 6–24). On average, a volume of 8.3 mL hydrogel was used to coat an implant. The most often used antibiotics were vancomycin and gentamicin at a concentration of 5% and 3.2%, respectively. Fifteen patients received an implant with a combined vancomycin and meropenem antibiotic coating; four patients received an implant coated with teicoplanin 5% or ceftazidime 5% or amphotericin B 5%, all in a second-stage procedure for previous infection. Eleven surgical site infections were observed in the control group and only one in the treatment group (6% vs. 0.6%; P = 0.003). No local or systemic side effects related to the DAC® hydrogel coating were reported and no detectable interference with implant osteointegration was noted. In the other multicenter, prospective study, 256 patients, undergoing osteosynthesis for a closed fracture, were randomly assigned, in 5 European orthopedic centers, to receive the antibiotic-loaded DAC® coating or to a control group, without coating. At a mean follow-up of

no detrimental effects of vancomycin-loaded DAC® or of DAC® alone [57].

antibiotic-loaded hydrogel.

190 Hydrogels

**7. Clinical results and applications**

may remain at ambient temperature for up to 4 h.

Periprosthetic joint infections (PJI) are associated with increased costs for public health systems, mainly due to additional surgeries, prolonged hospitalization, increased length of rehabilitation and increased use of antibiotics [64]. Moreover, PJIs are associated with an increase in morbidity and mortality [65]. Unless novel, effective measures are taken to reduce the incidence of surgical site infections (SSIs), these complications will become an accruing burden to the health care system in the next two decades [66, 67].

Cost-effectiveness of antibacterial coatings of joint prostheses can be calculated, comparing their direct and indirect hospital costs with those of unprotected implants, taking into consideration the expected surgical site infection rate and using a decision-analytic modeling approach, as previously described by Diaz-Ledezma et al. [68] and Kapadia et al. [69].

**Table 2** reports an algorithm used to calculate the overall economic impact of DAC® hydrogel coating. The following variables are included for calculation: average cost and number of primary joint replacements; average cost of the antibacterial coating per patient; incidence of PJI and expected reduction of infection rate with the use of the coating; average cost of PJI treatment and expected number of cases.

Various scenarios can be simulated with the reported algorithm, depending on the relative value given to each variable.

Considering the undiscounted price of DAC® hydrogel at our institution of € 585.00 per package and two packages of DAC® as the standard use per patient, it can be calculated that, if the


coating is able to reduce surgical site infection by 90% [60], DAC® is in economical balance if applied to a population of patients with an expected rate of septic complications (without the

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

http://dx.doi.org/10.5772/intechopen.73203

193

According to a similar calculation, if applied on a large scale, to a selected population of patients with at least one risk factor for infection and an expected incidence of infection, without the coating, of 5%, DAC® would provide, in a medium size country, like Italy (approximately 160,000 joint replacements per year), annual direct cost savings of approximately € 43,200,000 (or 1080 € per patient). An expected incidence of postsurgical infection of 5% applies to patients with at least one risk factor for infection, which is at least 25% of all patients

The present analysis is very conservative. One package of DAC® is in fact sufficient in the vast majority of primary implants. Secondly, recent studies point out how the long-term average cost of PJI is much higher than € 50,000, largely exceeding € 100,000 per patient [13]; finally, the algorithm does not include indirect costs, like those deriving from treatment complications, functional inability, work loss and compensation, medicolegal costs, increased mortal-

Biofilm- and implant-related infections represent a dramatic and increasing burden worldwide. Available data show that hyaluronic acid has a proven *in vitro* antiadhesive/antibiofilm effect against some of the most common pathogens, and HA has been used safely, alone or in combination with other polymers, with satisfactory results in different conditions associated with biofilm-related chronic infections. Clinical data in various applications, including dentistry, urology, wound management, dermatology and orthopedics, paved the way to the

The chemical derivatization of hyaluronic acid with polylactic acid allows the formation of graft copolymers, which, when contacted with an aqueous medium, can be used to produce hydrogels, like the recently CE-marked DAC®, with appropriate characteristics for easy preparation and application at the time of surgery. Resulting medicated hydrogel is transparent, easily spreadable over a surface, like a titanium prosthesis, and has a specifically designed duration; moreover, it has proven, peculiar, antiadhesive and antibiofilm capabilities. If required, it may also be easily loaded, at surgery, with antibacterial agents that will be released over the following hours or few days in effective high local concentrations. In fact, as a passive protective barrier, DAC® hydrogel has some limits. Among others, the antiadhesive/antibiofilm effect is limited and may vary, depending on the type of the microorganism, the bacterial load, the local environment, etc.; moreover, HA protection may be neutralized by the possible ability of some bacteria to produce hyaluronidase, an enzyme that catalyzes the degradation of hyaluronic acid [52], while collagen and hyaluronan may even become possible ligands for microbial attachment in particular situations, or the coating can be covered by other host's proteins to which bacteria may anchor [72, 73]. To overcome some of these limits, possible loading of

possible use of HA as a protective coating barrier of implants.

coating) of 2.6% (**Table 3**).

undergoing joint replacement [70, 71].

ity rate and quality of life reduction.

**9. Conclusions**

**Table 2.** Algorithm used to estimate the economical impact of antibacterial coating technologies.


**Table 3.** In this simulation, assuming an average cost of primary joint replacement of € 8000 per patient, an average cost of DAC® of € 1170 per case (i.e., two packages per patient), an expected reduction of postsurgical infections by using the coating of 90% and an average cost of PJI treatment of € 50,000 [6, 74], it can be calculated that DAC® is in economical balance if used in a population of patients with an expected periprosthetic infection rate, without the coating, of 2.6%.

coating is able to reduce surgical site infection by 90% [60], DAC® is in economical balance if applied to a population of patients with an expected rate of septic complications (without the coating) of 2.6% (**Table 3**).

According to a similar calculation, if applied on a large scale, to a selected population of patients with at least one risk factor for infection and an expected incidence of infection, without the coating, of 5%, DAC® would provide, in a medium size country, like Italy (approximately 160,000 joint replacements per year), annual direct cost savings of approximately € 43,200,000 (or 1080 € per patient). An expected incidence of postsurgical infection of 5% applies to patients with at least one risk factor for infection, which is at least 25% of all patients undergoing joint replacement [70, 71].

The present analysis is very conservative. One package of DAC® is in fact sufficient in the vast majority of primary implants. Secondly, recent studies point out how the long-term average cost of PJI is much higher than € 50,000, largely exceeding € 100,000 per patient [13]; finally, the algorithm does not include indirect costs, like those deriving from treatment complications, functional inability, work loss and compensation, medicolegal costs, increased mortality rate and quality of life reduction.
