Advances in biomaterials engineering and assembling/conjugation with biological agents allowed for application of novel wound healing therapies. Properly engineered hybrid biomaterials allow for accelerated recovery of damaged tissue by interfering with the wound healing process at the molecular level. Typically, two approaches for assembling active agents with biomaterials in wound repair are distinguished: (i) permanent immobilisation of the active agent onto polymeric matrix, and (ii) physical encapsulation of the active agent in the polymeric delivery system (matrix or template). The former approach involves chemical or enzymatic binding between the components where the active agent acts from the platform without being released to the wound. The advantage of this approach is the minimisation of the side effects due to the accumulation of immunoreactive compounds at the wound site, i.e. overdoses. The second approach is achieved by simple loading (impregnation) or encapsulation for programmed release of active agent [18]. If the delivery of an active in a consistent and sustained fashion over long periods of time is assured, the possibility of adverse effects and frequency of the dressing change also decrease.

Polymeric scaffolds that provide slow release of growth factors and cytokines have demonstrated the ability to attract cells through local signalling processes and stimulate the regenerative processes [82, 83]. Additionally, if these bioentities are integrated with biomaterials with beneficial for wound repair properties, enhanced wound healing properties to target more significant clinical utility are expected [84]. Among various biopolymers, gelatine, alginate, collagen and hyaluronic acid have been thus designed into gel matrices, porous sponges and microparticulate systems and used to deliver growth factors while maintaining their activity [85–89]. In one of the first studies of this type, a bilayer dressing comprising gelatine sponge and elastomeric synthetic polyurethane membrane used as the external layer was loaded with bFGF encapsulated in microparticles to achieve prolonged release [90]. The application of this hybrid wound dressing provided an optimum healing milieu for the proliferating cells and regenerating tissues in pig’s skin defect models. Actually, most of the growth factors and cytokines are proteins that easily interact with other biopolymers, which makes the choice of an appropriate (bio)material critical to achieve enhanced and sustained release, and thus its action at the wound site. In one unicentre randomised control trial the autologous PRP was evaluated in the combination with a protease modulating Promogran^®. The results in 51 patients with diabetic foot ulcers (17 of whom received the combined therapy) showed that this combination reduced the ulcer area more than that when compared with the dressing or PRP alone, suggesting a synergistic interaction between these components [91]. Nevertheless, prior to the widespread clinical use, the integrated growth factors/active dressing therapies need to be optimised and further validated for management of different types of difficult to treat wounds, by assessing their potential in larger, multicentre clinical trials.

Both synthetic and natural polymers have been also investigated and continue to be evaluated as platforms for immobilisation or delivery of active agents. There are numerous examples of polymers that have been mixed with antimicrobial/antiseptic substances to develop antimicrobial dressings and enhance healing of many wound types: fibrous hydrocolloids, poyurethane foam films and silicone gels were combined with silver [92, 93]; antibiotics were impregnated onto various polymer matrices for their delivery in wounds such as gentamycin from collagen sponges [94], ofloxacin from silicone gel sheets [95, 96], and minocycline from chitosan [97] and chitosan-polyurethane film dressings [98]; whereas PHMB-incorporated alginate antiseptic dressing is already marketed under the trade name of Suprasorb X + PHMB [99–101]. Another concept to manage difficult to treat wounds, e.g. chronic ulcers, is to control the activities of oxidative and proteolytic enzymes in wound bed by bringing down their elevated levels into the ranges found in acute wounds to allow healing to progress. However, this task must be taken with precaution, as the total inhibition of these enzymes is not desirable because of their role in the reconstruction of the ECM and wound progression towards closure. In one attempt, an active dressing specifically targeted towards reducing local levels of collagenases in non-healing wounds was developed using two biopolymers, bovine collagen and oxidised regenerated cellulose [44]. When placed in the wound bed, the collagen component acts as a decoy substrate for the proteases, whereas the oxidised cellulose dislodges metal ions from the active centre of these enzymes. Although this composite is still a state-of-the-art dressing on the market meant specifically for chronic wound treatment, it addresses only attenuation of the activities of some proteases at the wound site. The concept is currently being complemented by addressing other common factors influencing non-healing nature of chronic wounds of various aetiologies. For example, in our previous works, collagen, gelatine, chitosan, hyaluronic acid, chondroitin sulphate were used individually or as composite platforms, further upgraded with different plant polyphenols and thiol compounds targeting attenuation of both proteolytic collagenases and oxidative MPO, in addition to inhibiting bacterial growth. The produced biopolymeric platforms were either impregnated or permanently modified with active agents using chemical or enzymatic methods. For example, collagen was cross-linked with naturally occurring genipin to improve its biostability in physiological fluids prior to be impregnated with polyphenolic extracts from Hamamelis virginiana [102]. These extracts were previously found to be efficient scavengers of radical and non-radical reactive species, act as MPO substrates to prevent the accumulation of ROS and irreversibly inhibit collagenase [103]. The loading of plant polyphenols on sponge-like collagen dressings has been achieved on the bases of their ability to interact with proteins and polysaccharides [104, 105]. These interactions determine the release patterns from the biopolymer platforms and the activity of the advanced dressing [106]. Accordingly, in the case of polymer composites, capacity of the attenuation and especially duration of the inhibition effect are tuneable by the biopolymer composition and selection of the polyphenolic compound, being lower for polysaccharide than for protein platforms for which the effect is maintained up to 5 days [107]. In another study, a multifunctional bioactive chitosan/gelatine hydrogel additionally stabilised with plant polyphenols was achieved using laccase-assisted gelation [108]. Whereas gelatine facilitated coupling reactions and gelation, chitosan was used as an antimicrobial dressing platform. The phenolic compounds were covalently bonded on the hydrogels and exerted both: (i) structural function stabilising the dressing, and (ii) bio-activity inhibiting deleterious wound enzymes to stimulate the wound healing process. Permanent immobilisation of active agents reduces risk from overdoses and adverse immune effects at the wound site. The modification of polymeric surfaces in such way is a key aspect in biotechnology nowadays, including development of substrates for regenerative medicine. By alteration of the surface functionality controlled biochemical interactions with body fluids can be achieved. Thiolated chitosan, a biodegradable conjugate obtained by different chemical coupling approaches, combines a series of interesting functions such as mucoadhesive [109], permeation-enhancing [110], in situ gelling and enzyme inhibition properties [111, 112]. This conjugate was further processed into functional nanoscale films/coatings built using a layer-by-layer approach for alternate deposition of oppositely charged polyelectrolytes [113]. Glycosaminoglycans, namely HA with different Mw and chondroitin sulphate, were used as counterions to cationic thiolated conjugates. The biopolymer thiolation degree was identified as a key factor to achieve control of the thickness/size of the multilayered films. In addition, tuneable inhibition/adsorption of the deleterious enzymes coupled to fibroblast attachment/proliferation was observed by ruling the biopolymer modification degree.

Nowadays, more than 3,000 types of dressings overwhelm the wound management market. The characteristics of the various types of dressings depend on the intrinsic properties of the polymers employed for their preparation. The resulting products may be used individually or in combination to absorb exudate, combat odour and infection, relieve pain, promote autolytic debridement (wound cleansing) and/or provide and maintain a moist environment at the wound surface. An ideal marketable wound dressing should: (i) allow debridement, (ii), provide and maintain a moist wound environment, (iii) allow absorption, removal of blood and excess of wound exudate, (iv) permit gaseous exchange (water vapour and air), (v) prevent infection, (vi) provide thermal insulation, (vii) possess low adherence to allow non-painful dressing change, (viii) protect the wound from trauma, (ix) be cost effective, and (x) be biocompatible.

Taking into consideration the above properties, wide range of polymer-based materials are available to match particular wound requirements. Unfortunately, no single dressing can accomplish all these goals. Thus, the election of the appropriate dressing to a specific wound type is a difficult task and depends on factors related to the product itself, patient’s health status, wound type and location, and economic parameters, as summarised in Table 14.1.

Nowadays wound dressings frequently comprise the combination of polymeric layers with different functions that provide to the dressing particular characteristics. Table 14.2 presents an overview of various types of most frequent polymer-based wound dressings available in the market.