Research ArticleSkin wound healing with composite biomembranes loaded by tiopronin or captopril
Introduction
Wound repair is a dynamic, complex and interactive process, where participate a variety of cells, extracellular matrix components and soluble mediators involved in the processes of angiogenesis, coagulation, inflammation, reepithelization, contraction and fibroplasia. An important determinant of wound repair is hypoxia. Acute hypoxia has been shown to induce wound healing. On the other hand, prolonged hypoxia results in delayed healing, whereas a huge amount of reactive oxygen species (ROS) is produced over a prolonged period of time (André-Lévigne et al., 2017; Hong et al., 2014).
Currently, numerous research groups are focused on fabricating novel and enhanced wound dressings by synthesizing and modifying biocompatible materials to reach faster wound healing (Lee et al., 2014; Cho et al., 2015; Janahmadi et al., 2019). Efforts are directed especially to the use of biologically derived materials such as chitin and its derivatives, which tend to accelerate the healing processes at molecular, cellular and systemic levels. Chitin is a readily available and inexpensive biological material isolated from skeletons of invertebrates and cell walls of fungi (Jayakumar et al., 2011). Chitosan (Ch), derived by N-deacetylation from chitin, is composed of β-(1→4)-linked-2-amino-2-deoxy-d-glucopyranose and 2-acetamido-2-deoxy-d-glucopyranose (Dai et al., 2011; Singh et al., 2017). Chitosan is a biocompatible, biodegradable, nontoxic, anti-microbial, non-antigenic and hydrating agent (Dai et al., 2011; Jayakumar et al., 2011; Singh et al., 2017; Iacob et al., 2018). During skin wound healing chitosan plays a role in hemostasis since it is capable of binding with red blood cells, which allows rapid clotting of blood. Chitosan gradually depolymerizes to release N-acetyl-β-d-glucosamine, which promotes proliferation of fibroblasts, helps in controlled collagen deposition and stimulates elevated level of natural hyaluronic acid synthesis at the wound site (Dai et al., 2011; Jayakumar et al., 2011). Moreover, it modulates the functions of inflammatory cells and consequently supports granulation and tissue organization. As a semipermeable biological dressing, it maintains a sterile wound exudate beneath a dry scab, optimizes conditions for healing, prevents dehydration, formation of scars and contamination of the wound (Dai et al., 2011; Jayakumar et al., 2011; Stephen-Haynes et al., 2014). Chitosan can be readily applied into hydrogels, beads, membranes, micro/nanoparticles, nanofibers, scaffolds and sponges for various types of biomedical applications such as drug and gene delivery, wound healing, cartilage, tissue, bone and skin engineering (Jayakumar et al., 2011; Dai et al., 2011; Singh et al., 2017).
Hyaluronic acid (HA) is a high-molar-mass non-sulfated glycosaminoglycan, which is present in the extracellular matrix of numerous tissues such as skin, synovial joints and periodontal tissues. It is another biopolymer with critical biomedical applications and participates in each phase of the wound healing process (Iacob et al., 2018). In inflammatory phase HA binds to fibrinogen to initiate clotting, enables migration of inflammatory cells, forms edema to allow cell infiltration, and inhibits migration of neutrophils to attenuate inflammatory response. In proliferative phase it accumulates fibroblasts at the wound site, fills in gaps in forming extracellular matrix, stimulates migration and proliferation of keratinocytes and metaloproteinases for angiogenesis. In remodeling phase it plays a role in creation of normal and pathological scars (Frenkel, 2014; Roehrs et al., 2016). It also contributes to scavenging of ROS derived from polymorphonuclear leukocytes, which are strongly involved in the pathogenesis of wounds, especially in the chronic ones. Based on its biological properties associated with its biocompatibility and biodegradability, many biomaterials derived from HA have been examined in biomedicine (Iacob et al., 2018).
Tiopronin or N-(2-mercaptopropionyl)-glycine (Fig. 1 left) is a low-molar-mass synthetic analogue of glutathione. Since the 1980s in Western countries it is administered by patients with cystinuria and rheumatoid arthritis. Additionally, in China tiopronin has been extensively used in treatment of numerous liver diseases, including fatty liver disease, drug-induced liver injury and viral hepatitis. It is also used in mercury and copper poisoning (Hall et al., 2014; Castañeda-Arriaga et al., 2016; Zhong et al., 2019). Tiopronin serves as a ROS scavenger and as a chelator of metal ions, which associates with its thiol group (Hall et al., 2014). Yue et al. (2009) showed that tiopronin inhibited puerperal lactation and prophylaxis of cysteinenephrolithiasis. It had cardioprotective effects against ischemia-reperfusion-induced contractile dysfunction in rat heart and hepatoprotective effects against acetaminophen toxicity in mice. McIntyre et al. (2006) showed cytoprotective effects of tiopronin in myocardial ischemia and reperfusion and may be administered as a nephroprotective agent for treatment of the cisplatin-induced toxicity.
The angiotensin-converting enzyme inhibitor (ACE) captopril (Fig. 1 right) is widely used in the treatment of hypertension and of congestive heart failure. Moreover, it inhibits the progression of chronic renal failure and of diabetic nephropathy. It was also reported to have antiinflammatory activity (Salvetti et al., 1985; Bartosz et al., 1997; Petrov et al., 2012). However, in the presence of redox-active transition metals the thiol group of captopril may be responsible for prooxidant rather than antioxidant properties (Salvetti et al., 1985). The results of Lapenna et al. (1995) showed that when captopril interacts with copper, both metal chelation and reduction by the drug participate in copper-captopril-dependent oxidative damage. On the other hand, the thiol group of captopril can be also involved in scavenging of radicals (Misik et al., 1993). Captopril reacts rapidly withOH (rate constant > 109 M−1 s−1) however it is unlikely that it competes with most biological molecules forOH because it can be achieved in vivo during therapy only at low concentrations. Captopril is also a powerful scavenger of hypochlorous acid. It is able to prevent formation of chloramines from taurine and α-antiproteinase inactivation by hypochlorous acid (Aruoma et al., 1991; Misik et al., 1993). It is not capable of inhibiting myoglobin/H2O2 or iron ions/ascorbate-induced peroxidation of lipids. Captopril did not remarkedly inhibit iron ion-dependent generation of OH from hydrogen peroxide (Aruoma et al., 1991). It has been observed that the treatment of various diseases related to free radical damage with captopril attenuates the injury (Petrov et al., 2012).
The aim of the study was to evaluate Ch/HA membranes in the absence and presence of thiol drugs such as tiopronin or captopril on rabbit skin wounds and to compare them with untreated rabbits. In addition, the aim was to evaluate the ability of tiopronin and captopril to scavenge reactive oxygen species.
Section snippets
Materials
Sources of HA, CuCl2·2H2O p.a. and NaCl p.a., ascorbic acid, tiopronin, captopril, deionized high-purity grade water, stock and working solutions made from them were used as published previously by Valachova et al. (2015). Sources of chitosan, NaOH, ethanol, glycerol, formaldehyde, and haematoxylin & eosin were published by Tamer et al. (2018a,b).
Crossbred male rabbits HIL (12, 3.0 ± 0.5 kg) from the Department of Toxicology and Breeding of Laboratory Animals at CEM in Dobra Voda, Slovakia were
Results and discussion
We evaluated the percentage of skin wound healing in ischemic rabbits within 15 days (Fig. 2). During three days in untreated animals (control, white column) and animals treated with Ch/HA membrane (red column) the skin wound healed up to 5.0 %. A bit faster healing was reported when examining the efficacy of Ch/HA/tiopronin (blue column) and Ch/HA/captopril biomembranes (green column). On days 6 and 9 the wounds healed markedly more rapidly using three-component biomembranes (blue and green
Conclusion
The incorporation of antiinflamatory drugs into CH/HA membranes positively affected the period of skin wound healing in rabbits. Both captopril and tiopronin were shown to be potent in inhibiting HA oxidative degradation.
Declaration of Competing Interest
The authors declare no conflict of interrest.
Acknowledgement
The study was supported by the grants VEGA2/0019/19 and APVV-15-0308.
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