Scheme 14.1
The concept of advanced wound healing products
Accelerating Wound Healing with Active Agents—New Therapeutic Trends to be Combined with Polymers
Growth Factors and Cytokines
Growth factors are naturally occurring substances, secreted proteins and steroid hormones, capable of modulating cellular processes during tissue regeneration. They stimulate migration, infiltration, proliferation, and differentiation of mainly fibroblasts and keratinocytes by a complex signalling network. Accordingly, the capacity for wound repair can be augmented through the well-guided treatment involving these factors [53, 54]. The most promising growth factors that require clinical testing are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The most known platelet-derived growth factor BB (PDGF-BB) is the only one successfully completed randomized double-blind clinical trials in conjunction with standard wound care [55], which led to FDA approval for treatment of diabetic ulcers in a gel form under the trade name Regranex®. Nevertheless, new trends are moving towards mimicking the natural ways of healing in order to bring to the injury site a set of biological supplements to accelerate the functional recovery of the tissue, instead of relying on single-agent therapies. For example, activated autologous platelet rich plasma (PRP), known as plasma rich in growth factors (PRGF-Endoret®), an autologous blood platelet concentrate product recently classified as a medication in Spain, which, when activated, releases a set of growth factors that stimulate the regenerative phase of wound healing [56].
Cytokines are small proteins that modulate the immune response to stimulate tissue remodelling. Cell signaling culminates in an inflammatory phase of healing, which large part is regulated by both pro-inflammatory and anti-inflammatory cytokines. Interleukin-1, which in vitro stimulates most of the human cells, was tested in pressure ulcer patients with inconclusive results [57]. Similarly, granulocyte macrophage colony stimulating factor (GM-CSF) has been also showed promising for wound treatment in vitro, mainly due to the stimulation of VEGF production [58]. Other studies have given encouraging results in clinical trials on patients with venous stasis ulcers [59] and diabetic-foot ulcers [60]. However, cytokines should not be considered individually, because in vivo they function in complex networks and cascades, frequently exhibiting antagonism (the effects of one cytokine may be inhibited by another cytokine). The overall outcome of a biological response during inflammation thus reflects the balance between pro-inflammatory and anti-inflammatory cytokines [61]. This makes a combined cytokine therapy, with optimal stimulatory factors for wound repair, an attractive intervention for chronic diseases in general [62]. Nevertheless, both in vitro and in vivo studies on optimal synergistic combinations, duration and additional adjuvant therapies are required to precede clinical trials in order to assess the full potential of cytokines as biologic wound supplements.
Antimicrobials and Antiseptics
As infections still remain a feared complication in wounds, the purpose of applying antimicrobial agents is mainly to prevent or combat microbial colonisation. Sustained delivery of antimicrobials, e.g. antibiotics and silver, to wound sites from polymeric dressings is a preferred option than topical administration that often results in toxic reactions due to overdoses. Regardless of the administration approach, these antimicrobials effectively reduce microbial bioburden in infected wounds. However, silver toxicity to mammalian systems is still not fully investigated [63], whereas the excessive use of both antibiotics and silver led to the emergence of bacterial resistance [64, 65]. Further widespread use of antibiotics/silver is not desirable because it can only further contribute to the risk of developing microbial resistance, ultimately weakening our ability to counteract infections.
Current alternatives to antibiotics are antiseptics, with different mechanisms of inhibition of bacterial colonisation and growth. Although not as efficient as antibiotics, antiseptics are less toxic, active against broader spectrum of microorganisms, whereas resistance to antiseptics occurs less frequently [66]. For example, polyhexamethylene biguanide (PHMB) is an antiseptic with very low risk to induce bacterial resistance. An example of PHMB in conjunction with polymers is Suprasorb X + PHMB dressing of Lohmann&Rauscher, a calcium alginate with physically entrapped antiseptic, released into the wound upon application due to swelling.
Enzyme Inhibitory Agents
Abnormal redox state during the prolonged inflammation in non-healing ulcers calls for the use of redox drugs. MMPs are a group of metalloenzymes, where the catalytic Zn2+ in the active centre is coordinated by a redox-sensitive cysteine residue. Displacement, e.g. upon oxidation, of the cysteine ligand leads to the activation of the enzyme [67]—a mechanism termed “cysteine switch”. The MMP activation/inhibition could be redox-regulated by e.g. thiol compounds affecting the sulfhydryl/disulphide state of the switch [68]. A non-specific regulation of MMPs activity could be achieved by zinc chelation. Since thiols combine metal chelating and redox functions [69], thiolated polymers are expected to control the activities of these enzymes via a combination of these two mechanisms. On the other hand, MPO is an oxidative enzyme able to produce HClO, overwhelming the natural shield of protease inhibitors, enabling their accumulation in the chronic wound site [70]. The prevention of MPO-derived HClO accumulation can be envisaged at two levels by: (i) using competitive amounts of substrates to avoid the enzyme chlorination activity and HClO production, and (ii) application of HClO scavengers. As thiols inhibit HClO production [71], the use of thiol-bearing compounds would be an integrated approach for attenuation of both oxidative and proteolytic enzyme activities.
Similar effects on both enzymes are expected using polyphenolic antioxidants. Plant polyphenolic extracts of varying structures from simple molecules to highly polymerised compounds are well-known for their antioxidant capacity and scavenging activity over free radical and non-radical reactive species [72], metal-chelating capability [73] and inhibitory activity over radical-generating enzymes [74]. Plant polyphenols also possess anti-inflammatory [75], antimicrobial [76] and wound healing promoting properties [77]. Some polyphenolic extracts are widely used in the therapy of skin conditions, skin damages such as burns, and as protective component in cosmetic formulations [78, 79]. Various polyphenolic extracts are reported as efficient inhibitors of both MPO [80] and MMPs [81].
Although majority of active agents are effective in preclinical models of dermal repair, most fail to demonstrate the healing improvements when applied topically or systemically in clinical settings. Their limited clinical success is attributed to short half-lives and lack of robust and approved delivery systems. Proper assembling of active agents with biocompatible delivery templates would ensure their stability during the application. For example, if the biopolymeric materials with intrinsic antimicrobial properties are upgraded with bioactive compounds to provide the biochemical stimuli in difficult to treat wounds, an integrated strategy for their efficient management could be achieved. Moreover, controllable enzymatic inhibition could be expected by tuning the degree of biopolymer functionalisation (e.g. biopolymer thiolation, dosed biopolymer impregnation with polyphenols). This would be a step forward towards the regulation of the optimal enzyme/inhibitors ratio necessary for healing. Additionally, if sustained delivery to targeted tissue compartments is achieved, prolonged effects may be expected with improved tissue repair outcomes. Currently, many novel systems based on synthetic and natural polymers are being developed and investigated as active agent delivery systems.
Next Generation Wound Dressings and Formulations Combining Polymers and Active Agents
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.
Polymer-Based Healing Solutions in the Market
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.
Table 14.1
Factors influencing the election of a wound dressing
Product-related | Patient-related | Wound-related | Economic-related | ||
---|---|---|---|---|---|
Conformability | Wound aetiology | Wound type | Superficial | Cost | Unit cost |
Fluid handling | State of continence | Full thickness | Treatment cost | ||
Sensitisation potential | Fragile or easily damaged skin | Cavity | Cost of alternative materials | ||
Odour elimination | Known sensitivity to medicated dressings | Wound description | Necrotic | Availability | On prescription |
Non-toxicity | Sloughy | In stores or pharmacy departments | |||
Antibacterial activity | Granulating | Inclusion in local formularies | |||
Haemostatic properties | Epithelialising | ||||
Permeability to tissue fluid and microorganisms | Full thickness | ||||
Ease of use | Wound characteristics | Dry | |||
Pain related factors | Moist | ||||
Heavily exuding | |||||
Malodorous | |||||
Excessively painful | |||||
Infected | |||||
Location/size |
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.
Table 14.2
Polymer-based wound dressings currently available in the market
Properties | Commercial name | Manufacturer | Polymer | |
---|---|---|---|---|
Films | Thin polyurethane semi-permeable transparent sheet bounded to acrylamide or with acrylic adhesive layer | Mepore | Mölnlycke | Viscose (cellulose) xanthate |
Skintact | Robinson | |||
Elastic, conforms to wound shape | ||||
Pain relief | ||||
Prevents scab formation | Cutifilm | Smith and Nephew | Polyurethane | |
Allows continuous inspection | EpiView | Convatec | ||
Autolytic debridement | ||||
Minimal capacity to balance moisture and fluid accumulation | Mefilm | Mölnlycke | Polyurethane | |
Opsite Flexigrid | Smith and Nephew | Polyurethane | ||
Indicted for partial thickness wounds | Allevyn | Smith and Nephew | Polyurethane | |
Flexipore | Activheal | Polyurethane | ||
Bioclusive | Systagenix | Polyurethane | ||
Release | Johnson & Johnson | Ethylene-methyl acrylate | ||
Cutinova Hydro | Smith & Nephew | Polyurethane | ||
Primapore | Smith and Nephew | |||
Melolin | Smith and Nephew | |||
OpSite Plus | Smith and Nephew | Polyurethane
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