**1. Introduction**

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Calorim, DOI 10.1007/s10973-012-2269-7 (2012)

Metal implants in the field of orthopaedic and trauma surgery have been used for a long time to restore joint function, reduce pain or stabilize fractures [1-3]. Both prevention of infection as well as integration of the implant with the host-tissue (mostly bone) are factors of concern. The most frequently used implants for these purposes are made of metallic alloys (for plates and nails for fracture repair and for total joint arthroplasties) and polyethylene (PE) (used in the articulating parts of a prosthesis).

Infection of orthopaedic implants and prostheses is a medical issue that has intrigued people since their very first use over two-and-a-half millennia ago. Since that early beginning, lack of fixation and infection has been the major problem with such medical devices. In many cases, it may result in serious discomfort, limb amputation, illness and in many cases it may have even resulted in death of the patient. Even after 2500 years of medical progression we are still not able to fully conquer these major health risks. Since they are not isolated to the field of orthopaedics and trauma, their multi-factorial character indicates the complexity of the problems concerning healthcare-associated infections (HAI) [4, 5].

The purpose of this chapter is to give an insight in the quest to decrease the percentage of infections and increase the amount of osteointegration by coatings on metallic alloys in the field of orthopaedic and trauma surgery. Finally an overview will be provided of the available methods to examine and evaluate the properties of coatings *in vitro* and *in vivo*.

© 2013 Odekerken et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Odekerken et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **1.1. Healthcare-associated infections and orthopaedics**

Healthcare-associated infections, also called nosocomial infections, are considered to be the biggest healthcare related complication worldwide. HAI annually affects over 600 million patients worldwide with approximately 4.1 million patients in Europe and about 1.7 million patients in the United States [6, 7]. These infections can be related to the cause of death of a considerable number of patients annually. Together with the tremendous economic burden of HAI, HAI is a major point of interest in medical research.


**Table 1.** Epidemiological data on HAI [6, 7].

With urinary tract infections as the most frequent implant related HAI in developed countries, orthopaedic implant infections is another major sub-populations within the multifactorial group of HAI (together with infections related to cardiovascular, neurological and gastroin‐ testinal interventions). Infections due to implantation of total hip and total knee prostheses account for about 2% of the HAI, without taking trauma implants into account [7]. Trauma implants or implants for fracture fixation and stabilization, like plates, screws and stabilizing frames, have been described to have an even higher risk for infection, mainly due to the fact that they are used to repair complex injuries and open fractures. Infection together with the eventual loosening of an orthopaedic implant explains the limited lifespan of an orthopaedic device (generally up to 15 years for an artificial joint [5, 8, 9]).

**Figure 1.** A schematic representation of "the race for the surface", between the bacterial biofilm colonization and eu‐

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The first stage of bacterial biofilm formation is the settling of a planktonic bacterium on the surface of the implant. After adhering to the surface, the bacterium starts to divide and encapsulate itself for protection against the host organism's immune response. This layer of protective matrix, mostly consisting out of polysaccharides, also shields the bacteria from effective antibiotic treatment. The first stage of the biofilm formation is complete and subsequently the present bacteria start to form colonies increasing the internal pressure in the biofilm, which starts to expand. At a certain point the bacterial load within the mature biofilm becomes so high that planktonic bacteria are released from the biofilm. These bacteria can then result in the infection of the surrounding tissue or in the expansion of the biofilm on a different location (Figure 1) [10-12]. Eukaryotic cell adhesion (e.g. adhesion of osteoblasts) on the other hand, can result in implant ingrowth by settling of the osteo‐ blast on the implant surface, followed by cell division and collagen matrix production. Eventual calcification of the collagen matrix allows bone apposition on the implant surface (Figure 1) [10, 12]. In general the inability of the body and its immune system to cope with infected implants is one of the biggest issues when implants are used for medical treat‐ ment. Due to infection, local bone resorption takes place, leading to bone loss and im‐ plant loosening. As such it is essential to treat the infection, avoiding the risk of tremendous damage to the bone and the bony peri-implant tissue. After removal of an infected implant,

karyotic cell adhesion with subsequent bone apposition on the implant surface.

Since the discovery of antibiotics, (implant) infections have been reduced and implant infections have become less lethal and can even be cured. Still, the extensive use of antibiotics has resulted in an increasing amount of resistant bacterial strains, which makes infections caused by those pathogens challenging. Medical device implantation remains troublesome also in the case of orthopaedic implants.

#### **1.2. The race for the surface**

After implantation of an orthopaedic device, a competition between bacterial colonization versus tissue integration takes place to conquer the surface of the implant. This phenomenon is often described as "the race for the surface" (Figure 1) [10, 11].

**1.1. Healthcare-associated infections and orthopaedics**

HAI, HAI is a major point of interest in medical research.

**Prevalence (%)**

device (generally up to 15 years for an artificial joint [5, 8, 9]).

is often described as "the race for the surface" (Figure 1) [10, 11].

Europe 4.1 7.1 3.7% (€) 7 < 5%

USA 1.7 4.5 5.8% (\$) 6.5 < 5%

**Area # Patients**

46 Modern Surface Engineering Treatments

**(million/yr)**

**Table 1.** Epidemiological data on HAI [6, 7].

also in the case of orthopaedic implants.

**1.2. The race for the surface**

Healthcare-associated infections, also called nosocomial infections, are considered to be the biggest healthcare related complication worldwide. HAI annually affects over 600 million patients worldwide with approximately 4.1 million patients in Europe and about 1.7 million patients in the United States [6, 7]. These infections can be related to the cause of death of a considerable number of patients annually. Together with the tremendous economic burden of

> **Death (%)**

Worldwide > 600 8.5 - 15.5 Up to 75% in South-East

With urinary tract infections as the most frequent implant related HAI in developed countries, orthopaedic implant infections is another major sub-populations within the multifactorial group of HAI (together with infections related to cardiovascular, neurological and gastroin‐ testinal interventions). Infections due to implantation of total hip and total knee prostheses account for about 2% of the HAI, without taking trauma implants into account [7]. Trauma implants or implants for fracture fixation and stabilization, like plates, screws and stabilizing frames, have been described to have an even higher risk for infection, mainly due to the fact that they are used to repair complex injuries and open fractures. Infection together with the eventual loosening of an orthopaedic implant explains the limited lifespan of an orthopaedic

Since the discovery of antibiotics, (implant) infections have been reduced and implant infections have become less lethal and can even be cured. Still, the extensive use of antibiotics has resulted in an increasing amount of resistant bacterial strains, which makes infections caused by those pathogens challenging. Medical device implantation remains troublesome

After implantation of an orthopaedic device, a competition between bacterial colonization versus tissue integration takes place to conquer the surface of the implant. This phenomenon

**Costs (billion)** **Neonatal death rate (caused by HAI)**

Asia and Africa

**Figure 1.** A schematic representation of "the race for the surface", between the bacterial biofilm colonization and eu‐ karyotic cell adhesion with subsequent bone apposition on the implant surface.

The first stage of bacterial biofilm formation is the settling of a planktonic bacterium on the surface of the implant. After adhering to the surface, the bacterium starts to divide and encapsulate itself for protection against the host organism's immune response. This layer of protective matrix, mostly consisting out of polysaccharides, also shields the bacteria from effective antibiotic treatment. The first stage of the biofilm formation is complete and subsequently the present bacteria start to form colonies increasing the internal pressure in the biofilm, which starts to expand. At a certain point the bacterial load within the mature biofilm becomes so high that planktonic bacteria are released from the biofilm. These bacteria can then result in the infection of the surrounding tissue or in the expansion of the biofilm on a different location (Figure 1) [10-12]. Eukaryotic cell adhesion (e.g. adhesion of osteoblasts) on the other hand, can result in implant ingrowth by settling of the osteo‐ blast on the implant surface, followed by cell division and collagen matrix production. Eventual calcification of the collagen matrix allows bone apposition on the implant surface (Figure 1) [10, 12]. In general the inability of the body and its immune system to cope with infected implants is one of the biggest issues when implants are used for medical treat‐ ment. Due to infection, local bone resorption takes place, leading to bone loss and im‐ plant loosening. As such it is essential to treat the infection, avoiding the risk of tremendous damage to the bone and the bony peri-implant tissue. After removal of an infected implant, the accompanying bone fractures, soft tissue infection, and inflammation result in fixation issues and an increased infection risk during revision surgery [13].

HA (Ca10(PO4)6(OH)2) have shown that TCP ceramics dissolve over 10 times faster in acidic and alkaline environments compared to HA [19]. Explaining the rationale behind the current

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Since the proposed use of HA as a coating, in the late 1980's by Geesink*et al.*[14-16], several implant designs have been used in the clinic, e.g. partially coated or fully coated hip implants. Fully coated implants achieved complete bone remodeling around the implant, with very good fixation properties. The major disadvantage of these fully coated implants was that in case of revision surgery (either for implant infection or component failure) removal of the implant resulted in massive bone trauma due to the fixation of the implant to the bone. By redefining the coating location to the taper only, a good fixation could be achieved with limited problems at the time of a revision surgery [15]. However this design allowed the formation of stress shielding due to the pressure of the stem against the cortical wall. Due to this strain an implant can get loose, resulting in bone loss or a cortical wall fracture. Still HA coatings sintered to an implant surface has proven itself to be the most successful implant coating made, with 20 years

There are several ways to coat a metallic alloy, like titanium or stainless steel, with HA. The techniques to coat such a metallic implant include; dip coating [21], sputter coating [22], pulsed laser deposition [23], hot pressing and hot isostatic pressing [24], electrophoretic deposition [25], electrostatic spraying [26, 27], thermal spraying [28], and sol–gel [29]. Some of these techniques are still experimental, thermal spraying, in particular. Plasma spraying is the most accepted method for the production of HA coatings [30]. Plasma spraying requires high temperatures which may damage the HA crystallinity and create unwanted or amorphous phases, with HA ablation from the coated surface as a possible result [28]. Every technique has its advantages and disadvantages. For example, the thickness, the bonding strength and the properties of the HA-composition may be influenced by the application technique. Techniques such as thermal spraying and sputter coating are used for surfaces or substrates (e.g. porous titanium implants) which are difficult to coat. Techniques such as electrophoretic deposition and sol-gel may coat more complex substrates such as porous alloys, still the production of

Although biomimetic HA coatings improve the osteoconductivity of metal implants, they do not influence the osteoinductivity. In general osteoinductive coatings are described as coatings which induce bone formation of undifferentiated cells in the surrounding tissue to ultimately promote osteointegration of bone to the coating (active coatings). In order to promote the differentiation of immature progenitor cells to an osteoblastic lineage, attempts to integrate functional biological agents such as growthfactors into biomimetic coatings have been realized [33, 34]. Several of these coatings have been studied extensively, the most important coatings

use of TCP for resorbable bone scaffolds and the use of HA for implant coatings.

of clinical experience [8, 20].

*2.1.2. Hydroxyapatite application methods for metallic surfaces*

crack free coatings remains challenging (Table 2).

**2.2. Osteoinductive coatings**

are described below.

#### **1.3. Implant coatings**

In order to decrease the amount of implant infections and prevent the implants from loosening, coatings can be applied to the surface of the implant. These coatings may vary from (antibiotic) releasing to non-releasing coatings. In general non-releasing coatings (like hydroxyapatite) are applied by thermal-processes, while releasing coatings (like RGD or antibiotic-containing coatings) are mostly applied to the surface by dip or spray coating, due to their limited thermal stability.

Since the principle of the "race for the surface" dictates that early tissue integration may also reduce the infection risk, a coating promoting tissue integration may also be regarded as a passive method to reduce the amount of infections. In order to promote this tissue integration, one of the biggest leaps forward in the improvement of implant fixation and "the race for the surface" in favour of eukaryotic cells might be the use of hydroxyapatite (HA) coatings on the surface of a metallic implant [12, 14-16]. Although in the beginning it was believed that uncemented prostheses, including the HA-coated implants, would have a higher infection percentage compared to implants fixated with an antibiotic-releasing bone-cement, long-term studies showed a comparable infection percentage and a longer survival in favour of the uncemented prosthesis [5, 17]. These HA-based coatings (and their derivatives) are still one of the most frequently used implant coatings in the field of orthopaedic surgery and trauma, resulting in improved implant ingrowth and a longer lifespan of the prosthesis [8]. A combined situation of a coating with both antimicrobial and osteoconductive properties, is yet to be found.
