Bioactive biomaterials for controlling biofilms
8.4 Biomaterial applications in medical devices
The use of biomaterials in applications linked to medical device use largely fall into three key categories:
1. extracorporeal applications , such as catheters, tubing and fluid lines, dialysis devices, ocu- lar devices, wound dressings etc.;
2. permanently implanted devices such as orthopaedic, dental or cardiovascular devices; and
3. temporary implants , such as temporary vascular grafts, arterial stents, scaffolds for tissue growth or organ replacement, degradable sutures, implantable drug delivery systems etc.
(Gilmore and Gorman, 2013).
8.4.1 Complications associated with indwelling medical devices While there have been significant developments and improvements in the field of bio- materials over the last 50 years, many of the complications associated with their use are yet to be eradicated. Issues such as mechanical complications, adverse biological
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responses to implanted biomaterials and biomaterial- and device- related infections, which have presented problems since the earliest use of materials in human medicine, remain issues associated with modern devices. Many of the possible issues arising from mechanical failure or biological adverse effects have been successfully addressed by materials development; new polymeric materials, biologically inspired materials and materials capable of modulating biological responses via surface modification or drug release have facilitated the production of devices with much greater levels of biocompatibility. However, potentially the most serious of these complications, i.e.
microbial colonization, biofilm formation and device infection, are yet to be suitably resolved, despite great industry interest and research into the issue. While progress has been made in minimizing the occurrence of infections for short- term applications, progress towards development of an ultimately infection- resistant biomaterial for long- term use in patients has been very limited.
8.4.2 Mechanical complications
As a response to the continuing demand for biomaterials which mimic the biological, chemical, functional and mechanical attributes of the host tissue and environment as closely as possible, significant advances in material design continue to be made, ensur- ing continued improvement to medical devices. Polymeric materials currently offer the greatest potential range of properties and characteristics, meaning they can be tailored to fit specific functional niches. This versatility continues to drive great popularity in the use of synthetic polymers for biomedical applications. However, once in situ a device is subject to a range of functional demands, which can cause particular wear on synthetic polymers. Whilst the specific demands vary according to, most prominently, the placement of the device within the body and its intended function, they can all contribute to mechanical failure by causing environmental stress cracking, material degradation, time dependent deformation (creep), brittle fracture or fatigue. Such degradation can incite the release of particles of material into the surrounding tissue or fluid, leading to the establishment of an inflammatory response in vivo . This neces- sitates device removal and is considered a mechanically- induced biological failure.
8.4.3 Biocompatibility
Biomaterials are distinguished from other commonly encountered materials by the fact that they are specifically designed to be in contact with host tissue and/or bodily fluids. As such, biocompatibility, which has been defined as ‘the ability of a material to perform with an appropriate host response in a specific application’ (Williams, 1987), is an essential characteristic. Since the formal definition of biocompatibility almost three decades ago, there has been an increased appreciation and understanding of the interactions between the material and host tissues at the implantation site. This formalized concept of ‘biocompatibility’ could now be more leniently described as
‘biotolerability’ (Holt and Grainger, 2012).
In general, all biomaterials implanted into tissues are considered to be ‘foreign bodies’, to which the host will elicit a Foreign Body Response (FBR) as shown in
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Figure 8.1 . The FBR is initiated by protein adsorption/desorption at the biomaterial surface, a process known as the Vroman effect (Horbett, 2004). Plasma proteins compete for occupation of the surface and, once adhered, proteins such as albumin, fibrinogen, complement, fibronectin and vitronectin, amongst others, modulate host inflammatory cell interactions and adhesion (Anderson and Patel, 2013). As such, these adsorbed proteins are linked to subsequent inflammatory responses and wound healing. The FBR is essentially a pathological condition at the implant site caused by abnormal and unresolved wound healing, and it is characterized by the persistence of inflammatory cells (particularly macrophages), implant- associated foreign body giant cell (FBGC) formation, and excessive fibrosis.
FBGCs are large, multinucleated cells formed by the fusion of macrophages adher- ent on the implant surface. With the implanted device being too large to clear from the body by phagocytosis, FBGCs release a battery of enzymes and reactive interme- diates, a processes known as ‘frustrated phagocytosis’, that culminates in a targeted assault on the implant surface (Anderson et al. , 2008). Over time the biomaterial may degrade, resulting in the failure of the implanted device. The excessive fibrosis associated with the FBR forms an avascular fibrous capsule around the implant isolat- ing it from surrounding tissues, the most well known example of this process being capsular contracture, a complication following breast augmentation.
While the pathological processes of the FBR are problematic when they occur alone, the FBR may also augment and exacerbate biomaterial- associated infec- tions. The adhesion of macrophages and FBGCs to the biomaterial surface has been shown to exhibit a reduced bactericidal capability. This is in part due to a respiratory burst upon adhesion to the material, after which the cell becomes exhausted and is unable to produce bactericidal molecules (Anderson et al. , 2008). The surface chem- istry of the biomaterial may also promote apoptosis (programmed cell death), render- ing the macrophage unable to attack foreign organisms present on the biomaterial surface. Material- directed apoptosis of adhered macrophages has been demonstrated
Figure 8.1 A timeline of events constituting the Foreign Body Response (adapted from Grainger, 2013).
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both in vitro and in vivo , the effect appearing more prominent on hydrophilic and anionic surfaces (Brodbeck et al. , 2001, 2002). There is also evidence of a localized immunosuppressive environment in the immediate vicinity of the material. The immu- nosuppressive cytokines IL-10 and TGF- β have been found to be expressed around the implant during the FBR, and it is thought that they protect the host from an over reactive immune response. However, the localized concentration of these cytokines may down- regulate certain leukocyte functions, inhibit bactericidal mechanisms, and increase the susceptibility to opportunistic biomaterial- associated infections (Higgins et al. , 2009). In essence, following implantation of a medical device the host immune response towards the biomaterial may predominate and allow opportunistic pathogens to gain a foothold.
Successful prevention of medical device- associated infection requires an in- depth understanding of interfacial mechanisms leading to bacterial adherence and biofilm formation, but it is also necessary to develop an understanding of the host responses to the implanted biomaterial, particularly the processes involved in the FBR, if truly
‘biocompatible’ and infection- resistant materials are to be developed.
8.4.4 Infectious complications of implanted medical devices Susceptibility to device- related infections is a characteristic of all implanted medi- cal devices. An understanding of how microorganisms colonize indwelling devices and rapidly establish sessile populations on device surfaces is therefore key to developing possible prevention methods. Microbial biofilms consist of a matrix of extracellular polymeric material (or ‘glycocalyx’) encasing surface- adhered popula- tions of microbes, controlled by ‘quorum sensing’, a gene regulation mechanism that is population density- dependent. Such development and regulation is a ubiquitous survival mechanism amongst microorganisms and the main method of microorgan- ism growth.
Critically, the use of medical devices is the greatest external predictor of healthcare- associated infections, with implanted devices linked to at least half of all cases of HAIs (Richards et al. , 1999). Many biomaterials in current use exhibit surface characteristics such as poorly controlled, dynamic interfacial responses in physiological milieu, surface charge, hydrophobicity and microrugosity which actually favour surface colonization by microbes. Whilst establishing the exact scale and cost (in terms of both mortality and economic impact) of infections associated with medical devices is difficult, some estimated rates of infection and attributable mortality for commonly implanted medical devices are outlined in Table 8.2 .
Factors which further increase the risk of implanted device infection include pro- longed hospitalization, multiple surgical procedures at the time of implant, remote infections in other body parts, surgery duration and the amount of tissue devitaliza- tion (Choong and Whitfield, 2000). The rising number of medical device- related infections can also be partially attributed to the overall increase in their usage and, additionally, the growing number of immunocompromised and critically ill patients requiring treatment involving such devices.
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