Chapter 13: New developments in functional medical textiles and their mechanism of action – Functional Textiles for Improved Performance, Protection and Health

13

New developments in functional medical textiles and their mechanism of action

J.V. Edwards,     ARS-USDAUSA

S.C. Goheen,     Pacific Northwest National Laboratory, USA

Abstract:

Functional medical textiles are undergoing a revolution in structural design. Medical textiles as non-implantables, implantables and extracorporeals are playing central roles in healthcare improvements enhancing and prolonging the quality of life. Developments in the design of materials that function at the biological–material interface address material biocompatibility and bioactive function. A deeper understanding of the physiological, biochemical and biophysical milieus of biomaterials is being achieved in critical areas like wound healing, implant biocompatibility, dialysis and pressure ulcer prevention, which coupled with advances in nanotechnology holds great promise for tissue engineering and areas of biomaterial design for wound healing and prevention.

Key words

biomaterials

medical textiles

biocompatibility

implantables

non-implantables

extracorporeals

chronic wound dressings

pressure ulcer

hemorrhage control

13.1 Introduction

The functional nature of medical textiles is implicit to its application and many medical textiles have a multifunctional capacity. Even throughout history we see more than a mere attempt to cover a wound to protect it from further injury (see Wound Management and Dressings by Stephen Thomas, London: Pharmaceutical Press, 1999). From the ancients emerged textiles that were treated with substances that are still being researched for their underlying folklore properties. As with most areas of modern technology that address critical needs for mankind, exponential growth of functional medical textiles is drawing upon an interdisciplinary vision that challenges the textile and biomaterials scientist with new approaches to design based on mechanism of action. This chapter addresses some of the current ideas in medical textiles in the areas of non-implantables, extracorporeals, and implantables.

13.2 Extracorporeals and implantables

Extracorporeal medical textiles are used in mechanical organs such as hemodialyzers, artificial livers and mechanical lungs. Hemodialyzers provide blood purification for end-stage renal failure, and the use of other artificial organs as temporary replacement of or as a supplement to the lung or liver. The aim then with these types of artificial organs is to provide restoration of homeostasis within the body due to lack of blood oxygenation or a metabolic crisis due to acute liver failure. Implantable fibers include materials placed in the body that are used for wound closure or replacement surgery. Some of the considerations that are involved in determining the biocompatibility of the textile material with the body are (a) biodegradability, (b) non-toxicity and (c) fiber size, porosity and tissue encapsulation.

The boundary between extracorporeal medical devices and implantable devices will likely become thinner with advances in understanding the role of nano-biomaterials in tissue engineering, which is creating the potential to regenerate tissues and organs, for example artificial bladders, cornea and engineered skin. Nanostructured synthetic matrices and biopolymers show promise to be the next generation of biomaterial scaffolds. In this regard, natural polymers including collagen, fibronectin and hyaluroinic acid are viewed as superior to some traditional synthetic polymers used in tissue engineering. Moreover, understanding the design and role of biomaterials in three-dimensional spatial cell organization and interaction with the extracellular matrix (ECM) is an expanding topic where the role of fiber functionality is being examined in tissue engineering. Nanofiber scaffolds that will make their way into artificial organs and tissue engineering are being developed through advances in electrospinning, phase separation and self-assembling biomolecules.

13.2.1 Artificial kidney

An interesting pictoral history of dialysis can be found at http://www.homedialysis.org/learn/museum/. The kidney was the first organ to be substituted by an artificial device as well as the first successfully transplanted organ [1]. Renal replacement therapy for end-stage renal disease occurs now almost exclusively with hollow-fiber dialyzers [2]. Highly efficient hollow fibers have replaced coil or laminate in dialyzer devices. The cross-section of a hollow-fiber-type dialyzer consists of 4000–20 000 hollow filaments having an external diameter of 200–300 μm. Blood flows inside of the fibers and the dialysate flows outside of the fibers. Kidney dialysis mimics the ability of the kidney to remove wastes from the body including urea and albumin. Through diffusion small molecules or solutes are removed with sequential mass transfer from the dialyzer blood compartment through the membrane and into the dialysate compartment. A challenge in efficient dialysis is selective removal of proteins 10–30 kDa. Thus more efficient dialysis membranes need to be designed where proteins of MW around 20 kDa are removed while proteins around 70 kDa are allowed to remain in the blood compartment. Hemodialysis has also been shown to lead to chronic inflammation which is characterized by the presence of pro-inflammatory cytokines [3]. Moreover, pro-inflammatory cytokines have previously been shown to be released in vivo and in vitro when exposed to cellulose membranes. However, removal of large-scale toxins and cytokines has been reported through the use of continuous renal replacement therapies (CRRT) with high-flux, highly permeable biocompatible dialysis membranes [4]. In addition, Klein et al. [5] reported on a method for capturing anti-(Galα1–3Gal) antibodies formed from hyperacute rejection of pig xenografts by immobilized Galα1–3Gal oligomers derived from carrageenan. The use of bioactive epitopes containing galactose in an α–1–3 linkage were obtained from γ-carageenan oligosaccharides which were immobilized on hydrazide-modified microporous nylon membranes. These subsequently were shown to decrease human anti-(Gal-α-1–3 Gal) antibody level in normal human plasma. Layers of needle-punched fabrics varying in density have been reported to efficiently remove waste materials as an alternative in dialyzer filters [6].

Solute removal is the key function of the hollow-fiber dialyzers. Cellulosic materials are used in 80% of the dialyzers with very good permeability for low molecular weight substances. Cellulosic membranes are particularly suitable for diffusion-based dialysis with efficient removal of water-soluble uremic solutes like urea and creatinine. Cuprophan is a regenerated cellulosic membrane which is the material of choice in kidney dialysis due to the highly efficient and selective removal of urea and creatinine while retaining nutritive molecules such as vitamin B-12 in the bloodstream [7]. Cuprophan membranes have been shown to be more reusable than polysulfone and associated with fewer incidents of hypotension [8]. Cellulosic high efficiency dialyzers have very high diffusive permeability values for small solutes but low water permeability [1]. Synthetic membranes, on the other hand, which include polysulfone, polyamide and polymethylmethacrylate, were initially formulated with high water permeability in response to concerns about selective solute removal and a need to achieve higher filtration rates. The pore size and pore distribution have been characterized recently for the manner in which distribution influences a membrane’s sieving properties [6]. By contrasting the pore size distribution with the sieving coefficient versus molecular weight profile for membranes an optimal cut-off similar to the native kidney may be attained [9]. For example, a draw back with high permeability membranes can be albumin loss if the pore size is too large and the distribution of pores is too broad.

Since diffusion is the main mass transfer mechanism for removal of small molecules in hemodialysis, mass transfer resistance to biological flow rate is quantified by blood compartment resistance, resistance due to the membrane itself and dialysate compartment resistance. Solute removal of urea, creatinine and phosphate from blood occurs only during hemodialysis from plasma water, thus mass transfer from the red blood cell fraction of water to the plasma water must occur. When the percentage of red blood cells increase in whole blood (increased hematocrit) there is a relative sequestration of solute with low red blood cell membrane diffusivity. In the dialysate compartment improved mass transfer efficiency has been achieved by improved membrane designs. Among the new textile designs that influence hollow-fiber perfusion of dialysate is fiber bundle spacing. Improvements in the membrane surface area available for mass exchange during dialysis have been addressed with spacer yarns and specific fiber undulation patterns in this way. Ronco et al. measured the effect of ‘microcrimping’ and spacer yarns on small-solute removal and dialysate flow distribution, and it was found the urea clearances were higher for dialyzers with microcrimped fibers and spacer yarns [10]. Thus both of these approaches increase the effective membrane surface area, thus improving on dialysate flow distribution.

13.2.2 Bioartificial liver

The liver has enormous regenerative potential, and it has been recognized that it may be possible to regenerate sufficient amounts in vitro to make tissue engineering a viable clinical alternative to transplantation [11]. A variety of approaches have been tried in this regard, and these include culturing with growth factors and three-dimensional scaffolds in bioreactors. The extracorporeal liver assisted device (ELAD) containing porcine hepatocytes circulates a patient’s plasma through a bioreactor that contains active hepatocytes [12]. Hepatocytes carry out many vital functions including catabolic reactions and detoxification. Some of the membranes used in the ELAD are similar to those used in kidney dialysis including cuprophan, hemophan and polysulfone. Blood from the patient flows through the cartridge where the device is designed to filter and purify the patient’s blood through membranes containing the cells and then back into the patient similar to kidney dialysis. Although mature hepatocytes have been seeded in implantable artificial livers using biocompatible matrices the transplantation functionality and efficiency in animals requires considerable improvement before moving into the clinic [13].

13.2.3 Mechanical lung

Mechanical lungs with microporous membranes consisting of polypropylene hollow fibers exchange gases including O2 and CO2. Thus the gases pass through the pores of polypropylene hollow fibers but are not bubbled through the blood at extremely low pressure as has been done in the past. Closed-loop mechanical ventilation has the potential to provide more effective ventilatory support to patients with less complexity than conventional ventilation [14]. Microporous polypropylene hollow fiber is currently used for the manufacture of artificial lung membranes that exchange gases with blood but offer some hydrophobicity since polypropylene fibers exhibit comparatively good compatibility with blood and good gas permeability. Oxygen permeates the micropores of the fiber whereby the pressure gradient between blood and oxygen is near zero allowing red blood cells to capture oxygen by the diffusion process. The mechanical lung is principally used to replace lung function during heart surgery, and problems in its longterm use have been encountered due to a need for better membrane materials to prevent leakage of blood plasma.

13.3 Structure and composition: role of functionality in implantables

13.3.1 Biocompatibility

It would not be fair to say that the role of biomolecules in textile biocompatibility is fully understood. Rather, biomolecules and textiles are both so extremely diverse that all possible interactions are overwhelmingly extensive. But some basics can be discussed. It is well known that polymers and biopolymers interact partly due to their ionic and hydrophobic characteristics. Polar regions of biomolecules by intuition should be attracted to polar regions of textiles. Anions are attracted to cations, and hydrophobic regions are attracted to hydrophobic regions on the two types of molecules. As long as the solvent is aqueous, the hydrophilic (polar) moieties of the fibers and biopolymers, however, are often more attracted to water than to one another, and this is one feature that is commonly taken advantage of in the design of biocompatible fibers. Indeed, it has long been recognized that high water levels in a biomaterial provide a low interfacial free energy with blood and thereby reduce protein adsorption and cell adhesion on the surface [15].

Biocompatibility of materials that is understood well enough to control the interactions between the material and the surrounding biological milieu is a goal of biomaterial science. The issues that are involved in controlling the interactions between a living system and an implantable material are complex. To attempt to briefly enumerate some of the effects that are included in biocompatibility the following may be considered:

(a) The interfacial free energy [16], which involves the surface tension at the interface of the material and the biological fluid or tissue and the resulting dispersion and polar contributions of the interfacial free energies from protein adsorption, as well as the role of interfacial properties on cell adhesion. Thus, minimum interfacial free energy would result from increasing the polar surface free energy of the material.

(b) The hydrophilic versus hydrophobic balance on the surface of the fiber. Hydrophobic surfaces tend to adsorb larger amounts of proteins than hydrophilic ones and it is thought that more hydrophilic surfaces would be more biologically compatible [16]. Thus wettability is one of the most important parameters in biomaterial design.

(c) Chemical structures which include the nature of charge. For example, anionic surfaces tend to benefit biocompatibility from a standpoint of complement activation [17], albumin adsorption and macrophage distribution [18] or cell toxicity with respect to amines and their quaternary, secondary or primary structure [19].

(d) The types and density of charge which cover the surface of a polymer can affect cytotoxicity. For example, Fishcer showed that the charge/monomer ratio of cationic polymer was directly proportional to their cytotoxicity where poly(diallyldimethyl ammonium chloride) (PDDA) was the most toxic and cationized albumin was the least toxic [20]. In addition it has been shown that certain cationic polymers like polybrene, protamine and poly-l-ornithine cause activation of the complement system whereas negatively charged polyanions like dextran sulfate, polyvinyl sulfate, chondrotin sulfate and poly(inosinic acid) inactivate C1 or C2 components of the classical pathway of complement activation [17]. Charged surfaces have been found to promote bone formation [21] and Anderson et al. showed that hydrophilic anionic biomaterials induce apoptosis of adherent macrophages [22].

(e) Both molecular weight and conformational flexibility of the polymer influence biocompatibility. For example, lower molecular weight PEG coated surfaces show minimal protein adsorption, and polycations with a globular structure have good biocompatibility, whereas polymers with a more linear or branched and flexible structure, that is polylysine, showed a higher cell damaging effect [20].

(f) Surface patterns have been found to generate different responses of a biological system and self-assembling monolayers have been studied for their use in fabricating 3-D nano and micro structures [23]. Surface roughness has been found to influence thrombogenicity.

13.3.2 Cardiovascular implantables

In recent years implantable textiles have been increasingly designed with a biologically active component. Implantable textiles have been designed with specific functions compatible with the surrounding tissue. The functions have been targeted to blood flow and cardiovascular pressure as well as the forces and interactions of surrounding tissue. These include sutures for dermal and tissue repair, fabrics that have traditionally been employed in heart repair as reinforcement meshes, vascular grafts, velours for blood contacting surfaces, fiber reinforcements for hard and soft polymer bone and ligament prosthetics and intraocular lenses. The usefulness of actual biologically active molecules as a part of the fiber’s function in a tissue environment has been explored. Research in this area is a model for bridging bioactive molecules on fibers with performance textiles. Modern drug design approaches are based on enzyme and cell receptor recognition principles, and the analogous development of pharmacologically active molecules on textile fibers is targeted to biological recognition originating on the textile fiber. The concept of a bioactive fiber with pharmacological activity has been developed with implantable textiles in the cell adhesion domain.

The functionality of materials like polyester (PET) and expanded polytetrafluoroethylene (ePTFE) has been studied in the context of vascular grafts for replacement of diseased or damaged arteries for over 40 years [24]. PET and ePTFE are constructed into different fabric motifs suitable for vascular grafts and can be made into sheets, tubes and specific tailored forms. Since these fabrics are exposed to a wide range of stresses like bending, expansion, compression, rotation, and shear they have been extensively studied in both woven and knitted motifs for their failure modes. For example, burst strength, which is the ability of the fabric to resist internal pressure caused by blood flow and kink resistance, is affected by thread count. Bursting is also a potential problem where seams exist; however, ePTFE grafts are frequently modified with segmented or spiral rings. In addition it is necessary to obtain a balance between the strength that higher thread count affords and the loss in flexibility [25]. The thickness and tensile strength of the fabric are also important for the functionality of the graft such that thickness affects overall volume change of the device as well as porosity, permeability and kink resistance; whereas tensile strength affects the ability of the fabric to withstand the puncture of a needle, that is if the woven PET is too thin or does not have a high enough thread count the force of the sutures holding the stent in place on the graft wound result in a progressive tear [26].

13.3.3 Implantable biomaterials for tissue engineering

Biomaterials provide a three-dimensional structure for functional tissue to and from cells based on delivery of cells and mechanical support during tissue development. Bioactive molecules may be added to promote cell adhesion and proliferation or regulate cellular function. Three classes of biomaterials are used in tissue and organ engineering; these include proteinaceous and carbohydrate biopolymers – collagen, alginate, hyaluronic acid and chitosan; acellular tissues matrices including bladder and small-intestine submucosa; and synthetic polymers including polyglycolic acid (PGA), polylactic acid and polylactic-co-gly colic acid. The advantage of naturally occurring materials is their biological recognition. On the other hand synthetic polymers are advantageous due to the control in improving biocompatibility through design and manufacturing.

Electrospinning

Due to the fibrous structure of ECM proteins like collagen technologies including electrospinning, self-assembly and phase separation have been developed to achieve biomimetic properties conferred to tissues and organs using naturally occurring and synthetic materials. With electrospinning a non-woven material with nano-fibrous properties can be achieved that is not possible with other textile technologies. This is done with a polymer solution containing a spinneret, electric field and a target collector. A charged jet of polymer solution under the influence of an electric field is pulled in a straight line. As the jet diameter is reduced under a spiraling path due to electrical instability, and with solvent evaporation, a non-woven fibrous mat is collected. Various cells proliferate and maintain their integrity on nanofibrous materials consisting of collagen, silk, fibroin and fibrinogen and synthetic polymers like poly(glycolic acid) (PGA), poly(lactic acid) (PLLA), poly(lactic acid-co-glycolic acid) (PLGA) and poly(e caprolactone) (PCL). Electrospinning has been used to create highly porous scaffolds in various shapes, most recently in regenerative medicine, and has shown promise in application to functional nerve regeneration [27].

Self-assembly

Self-assembly on the other hand involves an autonomous organization of molecular components unique to the biomolecule without human devices and has led to the fabrication of novel biomaterials [28]. Biomolecules that form well-defined secondary structures like beta-sheet and alpha-helical conformation as is found with peptide, or micellar structures which form from lipids undergo self-assembly as a result of non-covalent bond forces including hydrogen bonds, ionic bonds and hydrophobic interactions. Collectively these non-covalent interactions can form tight networks of macromolecular structure useful in material design. Self-assembly to form biomaterials is discussed here in the context of bioactive peptides.

Phase separation

Phase separation utilizes the thermodynamic instability of a homogeneous, multicomponent system to lower the system’s free energy to achieve the equilibrium of the resulting material designed. Phase separation has been applied to the development of porous structures as tissue engineering scaffolds. For example, sublimation or replacement of a biomaterial and cellular system’s solvent to fabricate a nano-fibrous scaffold made of alginate with cells can result in a nano-fibrous pore wall in the shape of a human ear. Here the solvent or phase change process in material design is effectively doing the work to increase the surface area or implement pore distribution. Phase separation has been used as an accompanying technology to computer assisted design of tissue scaffolds [29]. This approach has been used to mimic body parts at size levels ranging from nano-fibrous ECM architecture to macro/micro-pores and patient anatomical shapes [30]. Along similar lines it has been found that scaffold materials can be printed into a desired shape using inkjet technology, and it has been shown that living cells can also be printed using this technology so that a three-dimensional construct containing a precision arrangement of cells’ growth factors and ECM can be printed.

13.4 The role of biomolecules in conferring bioactive function

13.4.1 Design of bioactive textiles

Numerous bioactive compounds including peptides, proteins, carbohydrates and lipids have been shown to retain their activity when conjugated to or formulated on textile fibers. Biologically active materials may be designed by conjugating bioactive compounds to a chemically reactive fiber with an understanding of retaining activity on the fiber. Four major classes of naturally occurring bioactive molecules include enzymes, peptides/proteins, carbohydrates and lipids, which offer various potential applications to performance textiles. These classes of bioactive molecules provide a myriad of potential high performance functionality for non-implantable, extracorporeal and implantable medical textiles.

Peptides

Peptides are perhaps the most versatile class of bioactive molecules within a diverse range of therapeutic and material applications. Peptides when attached to wound dressings in the form of textile-related technology have found applications in chronic and burn wounds. Peptide analogs of the bioactive sequences of elastin and laminin when linked to alginate promoted proliferation of fibroblasts. Synthetic peptides that mimic thrombin have also been linked to alginate to give rise to accelerated wound healing.

Self-assembling peptides have received increased attention for their potential application in implantable materials. Self-assembling peptides are found naturally in silk, wool and collagen. Silk is a natural fibrous protein derived from the silk worm cocoon which has been used as a medical textile for centuries due to its excellent mechanical and tensile properties. Silk consists of a core protein silk fibroin and a glue-like coating of sericin proteins. Silk is a potentially excellent scaffolding material for tendon and ligament tissue engineering [31]. The beta-sheet or alpha-helix conformational motifs of these self-assembling peptides confer nanostructural properties that lend themselves to use in implantable biomaterials. An interesting example of these conformational motifs that gives rise to self-assembly is found in spider dragline silk formed from beta-sheet crystals. This peptide motif converts to a partial helical structure when the sequence undergoes oxidation at the side chain thiomethylene of methionine to the sulfoxide thereby triggering a change in conformation. The resulting self-assembly gives rise to a biomaterial that could be used as a surface coating.

Self-assembling peptides (termed sapeptides) are being studied as biomaterials in regenerative medicine. Sapeptides generally have an amphiphilic structure that presents as hydrophilic heads and hydrophobic tails forming beta-sheets, and thus can pack together due to the hydrophobic interaction in water forming double-layered beta-sheet nanofibers [28] similar to those discussed above in silk. Interesting, sapeptides show nanostructures resembling those of the ECM. Since the self-assembling peptide is composed of amino acids that are the body’s natural building blocks they present negligible immune response and little inflammatory reactions in vivo.The self-assembling step is harmless and the versatility of the peptides similar to that of proteins.

Cell adhesion is important to cell spreading and migration and occurs within the ECM which is composed of proteins and glycoproteins like fibronectin, laminins, collagens and vitronectin. Cell surface receptors termed integrins bind ECM proteins to the matrix and mediate mechanical and chemical signals from it. In the early 1980s it was shown that the integrin binding and activation of these large proteins of the ECM resides in a short three amino acid sequence, arginine-glycine-aspratic acid (RGD) [32]. Since then the RGD sequence has been applied to textile surfaces through both covalent and non-covalent attachment. Dacron vascular grafts containing a 23 amino acid sequence with RGD (termed Peptite 2000) were prepared and used as a sewing cuff for artificial heart valves and vascular grafts. The RGD containing peptide promoted the formation of an endothelial-like cell layer on both PET and PTFE vascular grafts [33]. It is noteworthy that nanostructural scaffolds with bioactive motifs such as the RGD cell adhesion peptides have been considered for use in numerous tissue engineering approaches. For example Horii designed self-assembling scaffolds functionalized for osteoblast cultures with 2-unit RGD binding sequences [34]. Some sapeptides which are promising scaffolds have similarity to RGD, that is RAD mimics RGD, and they have been derivatized with bioactive sequences as well [35]. On the other hand a variety of applications of self-assembled peptide in tissue engineering include cartilage repair [35], neural regeneration [36], regeneration of cardiac tissue [37] and rapid hemostasis [38]. Interestingly the title, ‘ “nano neural knitting” a peptide scaffold for brain repair and axonal regeneration with return of functional vision’ [36], illustrates the promise of the technological applications of sapeptides. Since many of these scaffolds are beta-sheet conformation they do not prompt the body to mount an immune response, and they form a strong non-woven structure. Beta-sheet conformations self-assemble very rapidly and often form insoluble precipitates. Issues concerning the reproducibility resulting from random formation of beta-sheet self-assembled non-wovens, elastic architecture, and presentation to living tissue in high salt concentration to ensure more hydrophilic and aqueous compatibility need more work to fully realize the potential application of self-assembled peptides in tissue regeneration.

13.5 Non-implantables: wound dressings, pressure ulcers, hemorrhage control

Non-implantable medical textiles include those which are applied to the surface of the body. Examples of non-implantables include materials that are applied to or worn on the body for their hygienic, antimicrobial or decontamination properties; wound dressings used in wound and orthopedic care; hygienic incontinence devices which include disposable and non-disposable diapers, bed pads and high performance sheets used for pressure ulcer support surfaces; and protective clothing such as patient and medical personnel gowns and face masks. Improvements in the functional roles of each of these subgroups of non-implantables which will be treated here include (a) the development of improved battlefield and chronic wound dressings that target two separate parts of the wound-healing cascade; (b) development of decubitus-prevention devices for pressure ulcer patients and textiles that are compatible with pressure ulcer support mattresses; (c) improvements in creating antimicrobial surfaces against pathogenic bacteria viruses and fungi, and blood resistant protective environments.

13.5.1 Structure and composition: role of functionality in non-implantable medical textiles

Wound-healing materials

Progress in wound-healing science is reshaping the design of wound dressings. As shown in Fig. 13.1, wound healing is a complex cascade of molecular and cellular events [39]. During the coagulation phase following injury platelets initiate healing through the release of growth factors which diffuse from the wound to recruit inflammatory cells to the wound. Thus growth factors are responsible for the activation of immune cells, ECM deposition, collagen synthesis, and keratinocyte and fibroblast proliferation and migration. Neutrophils arrive on the scene early, and serve to clear the wound of bacteria and cellular debris. The arrival of neutrophils marks the onset of the inflammatory phase of wound healing, and under acute healing conditions lasts only a few days. However, in the chronic wound the period of growing neutrophil population is extended indefinitely. Inflammation is the second phase of healing and it is mostly regulated by cytokines which are secreted by macrophages. Cytokines control cellular chemotaxis, proliferation and differentiation. Macrophages also migrate to the wound site to destroy bacteria. However, an overabundance of cytokines and neutrophils prolongs the inflammatory phase and has a negative influence on healing. Granulation tissue, which consists of fibroblasts, epithelial cells and vascular endothelial cells, is formed about five days after injury. Fibroplasia is the last restorative stage of healing. Fibroplasia involves the combined effect of re-epithelialization, angiogenesis and connective tissue growth and it has been termed ‘a dynamic reciprocity of fibroblasts, cytokines, and ECM proteins’. In a healthy person healing occurs in 21 days from coagulation, and the remodeling phase consisting of scar transformation based on collagen synthesis continues for months following injury.

13.1 Stages of wound healing.

Pressure ulcers

Pressure ulcers occur when occluded blood flow due to interfacial pressure between the body and a support surface results in internal tissue stress leading to ischemia [40]. Ischemia involves impaired transport of nutrients and waste products to and from cells. During ischemia cells accumulate toxic metabolites that are deposited in the tissue and increase the rate of cell death. If external loading is not relieved where healthy tissue is allowed to recover from the pressure, tissue necrosis will occur. The rapidity with which this inflammatory process may occur and worsen to form a bed sore (sometimes within hours) depends on a variety of intrinsic and extrinsic factors. Shearing and friction also initiate bedsores by causing skin to stretch and blood vessels to kink resulting in impaired blood circulation in the skin. The incidence of pressure ulcers increases markedly in individuals over 70 years of age [41]. This in part is because the collagen content of the dermis, which makes the subcutaneous fat resistant to mechanical forces, decreases with aging [42]. Additional aging effects of the skin that can exacerbate the problem are decreased skin microcirculation [43] and decreased moisture content in the stratum corneum [44].

Pressure ulcers can progress through four stages of wounds that are clinically identifiable [40, 4446]. Stage I is characterized by redness, non-blanchable erythema, increased temperature and inconsistency of the epidermal layer of skin. Stage II is a partial thickness wound involving the dermis and characterized by swelling and formation of a blister, sore or shallow open crater. Stage III is characterized by full-thickness skin loss of the dermal layer down to subcutaneous fat tissue and it presents as a deep crater. Stage IV is a full-thickness skin loss down to the muscle or bone, presenting as a deep crater with visible muscle or bone and often accompanied by necrotic tissue and significant drainage.

Occlusive dressings

The concept that wounds heal best when kept dry was chiefly espoused in wound management up until the late 1950s because it was thought that bacterial infection could best be prevented by absorbing and removing all wound exudate. In the early 1960s Winter [47] and Hinman [48] showed that the rate of re-epithelialization increases in a moist wound versus a wound kept dry. Occlusion is the regulation of water vapor and gases from a wound to the atmosphere promoting a moist environment, which allows epidermal barrier function to be rapidly restored. Occlusion is a concept in wound management that prompted a revolution during the 1970s in the production of new types of wound dressings that are still being developed. The finding that moist wounds heal faster than when desiccated and that collagen at the interface of the scab and dermis impedes epidermal cell movement prompted the development of occlusive dressings for wound management.

Wound occlusion requires careful regulation of the moisture balance of the wound with vapor permeability to avoid exceeding the absorbency limits of the dressing. Thus, occlusive dressing types have been developed depending on the nature of the wound and accompanying wound exudate. The theory of moist wound healing led to approximately eight to nine separate types of wound-dressing materials and devices useful for different wound treatment indications. Each of the material types that represent these distinct groups have molecular and mechanical characteristics that confer properties to promote healing under specifically defined clinical indications, and are often used for pressure ulcer treatment depending on the stage and drainage of the wound. The following briefly outlines some of their properties.

Thin films

Thin films are semipermeable, polyurethane membranes with acrylic adhesive. They are used to treat minor burns, pressure areas (Stage I), donor sites and post-operative wounds. They should not be used to treat deep cavity wounds, third-degree burns or infected wounds.

Sheet hydrogels

Sheet hydrogels are solid, non-adhesive gel sheets that consist of a network of cross-linked, hydrophilic polymers which can absorb large amounts of water without dissolving or losing their structural integrity. Thus, they have a fixed shape in contrast to amorphous gels. They can be used as a carrier for topical medications, and absorb their own weight of wound exudate. They are permeable to water vapor and oxygen, but not to water and bacteria, and afford good visibility of the wound due to their transparent nature. They can be used for light to moderately exudative wounds, and in the autolytic debridement of Stages II and III pressure sores. They should not be used with heavily exuding wounds.

Hydrocolloids

Hydrocolloids are semipermeable polyurethane films in the form of solid wafers that contain hydroactive particles as sodium carboxymethyl cellulose, which swells with exudate and forms a gel. They are impermeable to exudate, micro-organisms and oxygen. Moist conditions produced by hydrocolloids promote epithelialization. Hydrocolloid dressings are good for the treatment of shallow or superficial wounds with minimal to moderate exudates. They should not be used on wounds with dry eschar or very light exudate.

Semipermeable foam

Semipermeable foam is a soft, open cell hydrophobic, polyurethane foam sheet 6–8 mm thick. Cells of the foam are designed to absorb liquid by capillary action. They are permeable to gases and water vapor, but not to aqueous solutions and exudate. They absorb blood and tissue fluids while the aqueous component evaporates through the dressing. Cellular debris and proteinaceous material are trapped. They are used for leg and decubitus ulcers, sutured wounds, burns and donor sites. They should not be applied to wounds covered with a dry scab or hard black necrotic tissue.

Amorphous hydrogel

Amorphous hydrogels are similar in composition to sheet hydrogels in their polymer and water make-up. However, amorphous gels are not cross-linked. They usually contain small quantities of added ingredients such as collagen, alginate, copper ions, peptides and polysaccharides. The gels are clear, yellowish or blue from copper ions. Viscosity of the gel varies with body temperature. They are available as tubes, foil packets and impregnated gauze sponges, and are used for full-thickness wounds to maintain hydration. They may also be used on infected wounds or as wound filler. They should not be used on heavily draining wounds, and improper use may lead to peri-wound maceration.

Fillers

Calcium alginate is one of the fillers that consist of an absorbent fibrous fleece with sodium and calcium salts of alginic acid (ratio 80:20). Dextranomer beads consist of circular beads, 0.1–0.3 mm in diameter, when dry. The bead is a three-dimensional cross-linked dextran, and long chain polysaccharide. Fillers are used with heavily exudating wounds including chronic wounds such as leg ulcers, pressure sores and fungating carcinomas. They are indicated for use in heavily exudating wounds (Stages III and IV), wounds containing soft yellow slough, including infected surgical or post-traumatic wounds. They should not be used with minimally exudating wounds.

Contact layer dressings

Contact layer dressings are porous, non-absorbent and inert and designed to allow the passage of wound exudate for absorption by a secondary dressing. These types of dressing are for shallow or superficial wounds with minimal to moderate exudates, and are not recommended for cleaning the wound.

Gauze packing

Cotton gauze is used both as a primary and secondary wound dressing. Gauze is manufactured as bandages, sponges, tubular bandages and stockings. Improvements in low-linting and absorbent properties have been made. Gauze is still a standard of care for chronic wounds. It fills deep wound defects and is useful over wound gel to maintain a moist environment; but it needs to be packed lightly. It may traumatize the wound if allowed to dry; therefore multiple small dry dressing wads in the wound cavity should be avoided. Cotton gauze may be wetted with saline solution to confer moist properties. It should possess a slight negative charge, which facilitates uptake of cationic proteases. It has absorbent and elastic properties for mobile body surfaces.

Wound vacuum assisted closure

Vacuum assisted closure is accomplished with polyurethane foam accompanied by vacuum negative pressure in the wound bed. The wound is filled with foam and sealed with a film. Vacuum tubing is inserted and used continuously. This approach is used on infected wounds and wounds with fistulae.

Chronic wounds

When wounds fail to heal the molecular and cellular environment of the chronic wound requires conversion to an acute wound so the ordinary sequential phases of wound healing can proceed. In June 2002 a meeting of wound-healing experts formulated an overview of the current status, role and key elements of wound bed preparation [49]. The subsequent reports in the literature from this meeting articulate well the concept of a systematic approach to wound bed preparation, which is based on an emphasis to decrease inflammatory cytokines and protease activity while increasing growth factor activity. Thus a challenge of current wound-dressing development is to promote the clinical action of wound bed preparation through addressing issues of high protease, and cytokine levels and increasing growth factor levels.

The design and preparation of interactive chronic wound dressings [50] has become increasingly important as part of a solution to addressing the critical worldwide health crisis of the growing number of chronic wound patients. In the United States alone there are over five million patients a year who suffer from chronic wounds due to the formation of decubitus bed sores brought on in the elderly nursing home or spinal chord paralysis patient. In addition, diabetes accounts for at least 60 000 patients annually who also suffer with foot ulcers. Since the mid-1990s the number of wound care products in the well-recognized groups outlined in Table 13.1 has expanded and new groups of products have also been marketed including tissue-engineered products [51, 52]. Recent efforts to develop wound dressings that do more than simply offer a moist wound environment for better healing have prompted most major wound-dressing companies to develop research and approaches on interactive chronic wound dressings. Interactive chronic wound dressings, which possess a mechanism-based mode of action, are targeted to biochemical events associated with pathogenesis of the chronic wound and are a part of good wound bed management.

Table 13.1

A list of functional characteristics and the corresponding structural properties needed to create a bed sore prevention incontinence device

Functional characteristics Structural properties
Fiber orientation to optimize patient skin health Fibers used as the weft of the material to impart smoothness are to be relatively more hydrophobic and finishes on fibers or cotton/synthetic blends having defined directionality are aligned to give less resistance to the stratum corneum of the skin and yield lower friction upon sliding. In contrast, fibers used as warp are more hydrophilic giving rise to more rapid moisture wicking away from the skin and sheet interface.
Low friction/high strength fibers The coefficient of friction will be low for the surface in contact with the patient and higher for the surface in contact with the bed support to keep the pad or sheet from moving and causing creases while imparting less friction and shear force to the patient’s skin.
Local deformation distribution/crease resistance Cotton spacer fabric composed of a surface contact layer that wicks moisture away from the skin while relieving shear, an internal core will provide a hydrophobic wicking channel that drains to a hydrophilic, highly absorbent core and is resilient to shear and pressure. Finishes on sheet or bed pad cover stocks will impart wrinkle resistance to promote better pressure redistribution.
Water absorbency Internal core of care sheet with cotton batting that is grafted with a super absorbent biopolymer, i.e. modified starch, polyethylene glycol, alginate, or similar polysaccharides.
Softness A ratio of cotton blended with compatible polymeric fibers or addition of a silicone softening agent to the fabric finish that impart a soft hand.
Antimicrobial An antimicrobial finish that provides a barrier to infection resulting from macerated skin or microbial contamination.

Skin substitutes, which are being increasingly used, contain both cellular and acellular components that appear to release or stimulate important cytokines and growth factors that have been associated with accelerated wound healing [52]. Some basic materials may also play a role in up-regulating growth factor and cytokine production and blocking destructive proteolysis. In this regard the biochemical and cellular interactions that promote more optimal wound healing have only recently been elucidated for some of the occlusive dressings. For example, certain types of alginate dressings have been shown to activate human macrophages to secrete proinflammatory cytokines associated with accelerated healing [53]. Interactive wound-dressing materials may also be designed with the purpose of either entrapping or sequestering molecules from the wound bed and removing the deleterious activity from the wound bed as the wound dressing is removed, or stimulating the production of beneficial growth factors and cytokines through unique material properties. They may also be employed to improve recombinant growth factor applications. Impetus for material design of these dressings derives from advances in the understanding of the cellular and biochemical mechanisms underlying wound healing. With an improved understanding of the interaction of cytokines, growth factors and proteases in acute and chronic wounds [5457] the molecular modes of action have been elucidated for dressing designs as balancing the biochemical events of inflammation in the chronic wound and accelerating healing. The use of polysaccharides, collagen and synthetic polymers in the design of new fibrous materials that optimize wound healing at the molecular level has stimulated research on dressing material interaction with wound cytokines [53], growth factors [58, 59], proteases [6063], reactive oxygen species [64] and ECM proteins [65].

Sequestration of wound proteases and approaches to treating chronic dermal ulcers

The prolonged inflammatory phase characteristic of chronic wounds results in an overexuberant response of neutrophils, which contain proteases and free radical generating enzymes that have been implicated in mediating much of the tissue damage associated with chronic inflammatory diseases. Since neutrophils mediate a variety of chemotactic, proteolytic and oxidative events that have destructive activities in the chronic wound, therapeutic interventions have been proposed based on the proteolytic and oxidative mechanisms of neutrophil activity in the wound. Neutrophils contain both matrix metalloproteases and cationic serine proteases, which are two families of proteases that have been associated with a variety of inflammatory diseases, and have been implicated as destructive proteases that impede wound healing. The presence of elevated levels of these proteases in non-healing wounds has been associated with the degradation of important growth factors and fibronectin necessary for wound healing [66]. There is also a synergistic effect of further oxidative inactivation of endogenous protease inhibitors which leads to unchecked protease activity.

A protease sequestrant dressing’s design for activity may be couched in a number of molecular motifs based on the structural features of the protease, which interferes with the healing process. The molecular features of the material may be targeted to the protein’s size, charge, active site and conformation to enhance selective binding of the protein to the dressing material and removal of the detrimental protein from the wound bed. Active wound dressings that have been designed to redress the biochemical imbalance of the chronic wound in this manner are composed of collagen and oxidized regenerated cellulose [67], nanocrystalline silver-coated high density polyethylene [63], deferrioxamine-linked cellulose [68], and electrophilic and ionically derivatized cotton [61].

13.5.2 Pressure ulcer prevention materials

As the population ages and the number of pressure ulcer patients increases [6971], there is now a critical need to fill a serious gap in effective pressure ulcer prevention textiles [72]. The medical textiles at the interface of patient skin and medical treatment support surfaces include bed sheets, patient clothing, under pads and incontinence devices. The interfacial forces of pressure, shear and friction act at this common boundary to break down skin, occlude blood flow and create ischemia or inflammation, ultimately leading to tissue necrosis and a chronic wound pathology that can often result in death [7375]. Pressure ulcers develop on the bony prominences of the body, and most pressure ulcer wounds are located on the sacrum or coccyx. Although there has been a huge effort in medicine to analyze and prevent bed sores with pressure relief support surfaces [76], efforts to control friction and moisture transport away from the patient’s body have been considerably less [77]. For example, there is little mention in the standards for minimum care or reimbursable services in the United States Medicare codes with regard to hospital bed sheet criteria, and there have been very few randomized controlled trials on the use of incontinence pads with support surfaces [78, 79] to prompt improvements in moisture management and skin and textile friction control. Moreover, the effect of existing absorbent incontinence pads on pressure management mattresses has been characterized recently for their substantial adverse effect on pressure redistribution [80]. Moreover, whereas treatment and prevention often overlap in the care given to pressure ulcer patients [81], many of the seven–eight types of occlusive dressings (discussed above) used for decubitus treatment have not been studied for their compatibility with under pads, bed sheets, patient clothing and support surfaces.

With a few recent exceptions, the work previously reported on decubitus-prevention care sheets [81] and bed sheets [82] is scarce. The patent literature has a few examples of inventions for friction and combined incontinence control in care pads [83] and sheets [84, 85]. However, a variety of factors need to be considered in design of improved hospital bed sheets, bed pads, incontinence devices and medical textile compatible surfaces. Table 13.1 outlines the structural properties required to give functional characteristics needed in care and bed sheets for improved decubitus prevention, and Fig. 13.2 illustrates the conventional design of incontinence devices and bed pads. Since the patient is in constant contact with the sheet or bed pad, these materials are very important in maintaining a proper microclimate. The skin can produce up to 1000 cm3 of perspiration an hour to maintain a constant body temperature between 33 °C and 35 °C which assures thermal comfort. Thus, perspiration should be moved to the outside, otherwise it condenses on the skin and within the sheet structure. It has been recently shown using corneometry in combination with friction experiments on a force plate that coefficients of friction (COFs) of skin against hospital textiles increase from very dry to normally moist skin by 33% [77]. Hence, skin abrasions and bed sores can have their origin in poor moisture management at the skin-textile interface. Although there have been a few recent biophysical and friction analysis tests directed toward understanding the interfacial forces of friction and pressure between skin and textiles, there have been very few literature reports on applying the concepts outlined in Table 13.1 to the design and testing of improved decubitus-prevention materials. Thus, there is great potential for improving medical textiles at the skin-textile interface in this regard.

13.2 Diagram of a bed sheet and non-woven care sheet designed to wick moisture away from a patient’s skin into an absorbent core while possessing a low coefficient of friction at the skin–textile interface. The design of incontinence devices for bed sore prevention is laid out in Table 13.1.

13.5.3 Hemorrhage control dressings

Half of all deaths on the battlefield are caused by uncontrolled hemorrhage [86, 87]. In addition, high blood loss can lead to hypothermia, multiple organ failure and infection [8890]. Thus, rapid hemostasis is essential for survival and recovery. The development of improved hemostatic agents for use in lethal extremity arterial hemorrhages has increased over recent years [91].

The US Army Institute for Surgical Research (USAISR) and the Uniformed Services University of the Health Sciences has outlined ideal properties needed in a battlefield dressing [92]. These include the following: (a) being able to rapidly stop large vessel arterial and venous bleeding 2 min after application when applied to an actively bleeding wound through a pool of blood; (b) no requirement for mixing or pre-application preparation; (c) simplicity of application by wounded victim, buddy or medic; (d) light weight and durable; (e) long shelf life in extreme environments; (f) safe to use with no risk of injury to tissues or transmission of infection; and (g) inexpensive. With this list of ideal properties the question arises: Is there any deployed product capable of stopping or reducing groin arterial bleeding and preventing exsanguinations that otherwise could not be controlled by the standard gauze dressing? The dressings evaluated by the USAISR were the Army Field Dressing (a cotton product of long-standing use), Quikclot, HemCon, and Fibrin Sealant. Surface area coverage, sealant efficacy, adherence and adsorption capacity are all important factors in this challenging area of hemostasis since the geometry and anatomical location of the wounds can vary greatly, and factors in to the success of patient survival. The Army Field Dressing, which is the standard field dressing used by the military consists of two layers of gauze that wrap densely packed cotton. It absorbs a large volume of blood, and the cotton strands stimulate platelet aggregation. The prohibitive price of Fibrin Sealant which consists of fibrinogen and thrombin ($500-$1000 per dressing) prevents widespread deployment of this type of dressing. Quikclot is a granular mineral zeolite that rapidly absorbs water in an exothermic reaction [92]. Some improvements on zeolite-impregnated dressings in the form of the kaolin-impregnated gauze (Quikclot Combat Gauze) were made. Bentonite (WoundStat) also rapidly halts clotting [93, 94]. Kaolin and bentonite are clay minerals which act as sealants; however, they do not produce an exothermic reaction. It is also noteworthy that recently the relative thrombogenic effects of these aluminum phyllosilicate clay minerals have been examined, and questioned for their in vivo safety [95]. However, it is important to understand their mode of action as blood flow sealants, and in clotting. Furthermore considerable concern was registered about systemic vascular thrombogenesis shown by bentonite granules since the material was tested as loose granules at the locus of the wound bed and resulted in occlusive thrombi. HemCon, which is principally chitosan as previously described, has strong tissue adhesive properties that seal the wound and stops bleeding through promotion of platelet aggregation [92]. TaumaDex employs starch microspheres which seal blood flow upon application through a molecular sieve-like mechanism [96]. Surface area coverage, sealant efficacy, adherence and adsorption capacity are all important factors in this challenging area of hemostasis since the geometry and anatomical location of the wounds can vary greatly, and is a factor in the success of patient survival.

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