Caffeic acid encapsulated 3D printed polycaprolactone/polyvinylpyrrolidone scaffolds for wound healing applications

Wound management is becoming a huge problem throughout the world and it is causing a major effect on the health-care budget of countries [1]. Wound healing is a process of growth and tissue regeneration at the site of wound. Lessening of pain and infection is the major purpose in the healing process of wounds [[2], [3], [4]]. Healing of wounds requires different types of cells and reaction mechanisms for the regeneration and replacement of injured and lost tissue respectively [5]. During healing of wounds, there are chances of infection by bacteria and airborne dust particles that slow down the healing process [6]. Wound dressings are becoming a common therapy for wound healing [[7], [8], [9]]. An ideal wound dressing should possess the properties like perfect biological activities of tissue regeneration and wound healing, biocompatible, biodegradable, non-toxic, less surface necrosis of wound surface, keep the wound warm and moist, protection of wound infection from infection, reduce the pain and cost effective [10,11]. Alongside, a wound dressing should also possess the property of removing exudate from wound and avoid maceration during gas exchange [12].

Wounds may appear in different shapes and sizes so trimming and overlapping of wound dressings takes time to cover the wound. Wound dressings with fixed composition of active ingredients are present in the market so they cannot be tuned by the users. So, 3D printing can be used as a solution for these problems [13]. 3D printed hydrogels scaffolds for wound dressings provide number of advantages like customization of doses according to individual needs, tailoring of dimensional properties (area, thickness, pore size) of wound dressing, simple drug loading process and effective oxygen penetration due to mesh size [14]. High mechanical strength, biodegradability, biocompatibility and 3D porous microstructures make these 3D printed scaffolds a best choice in the field of tissue engineering. These biomaterial scaffolds have been proven to be safe, durable and useful for repairing [15].

Biocompatible hydrogels from synthetic sources like polycaprolactone (PCL), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and natural sources like alginate, chitosan and pectin have widely been fabricated for their biomedical applications. PCL is a food and drug administration (FDA) approved linear polyester semi-crystalline biodegradable and biocompatible polymer [16] with mechanical flexibility, easy processing and low cost having wide range of applications in drug delivery systems, sutures materials, wound dressings and in scaffolds fabrication for regeneration of tissue [[17], [18], [19], [20]]. PCL is widely used to prepare patient specific scaffolds having appropriate size, suitable dimensions, shape, porosity, chemical composition because of its compatibility with 3D printing technology [21,22]. PCL is also considered as a preferred polymer for extrusion based 3D printing because of its melting temperature of 55–60 °C [23,24]. PVP polymer is a non-toxic, degradable and biocompatible with various applications in biomedical materials like wound dressings, tissue engineering and controlled drug release. It possesses high solubility in water and organic solvent [25]. PVP has been extensively employed in controlled drug delivery systems, artificial skin, tissue engineering and wound dressings [26]. PVP also has the ability of incorporating and releasing antibiotics in a controlled manner and possesses self-adhesive properties [27].

Incorporation of active therapeutic agents like antibiotics and antimicrobial agents into wound dressings enhance their ability to facilitate wound healing by improving the treatment and prevention of infection [28]. Caffeic acid (CA) is a compound derived from plants, and belongs to an important group of hydroxycinnamic acid [29], having both phenolic and acrylic functional groups [30]. It is present in several yields of plants like coffee, wine, wheat, olive oil, legume and also commonly present in the bark of Eucalyptus globulus [31]. CA possesses great anti-microbial activity against the pathogenic and chronic infection caused by microbes [32,33]. Caffeic acid (CA) has been classified as possible human carcinogen (Group 2B compound) based on animal trails by IARC [34]. CA has shown carcinogenic effect in the forestomach of F344 rats by causing squamous cell papillomas and carcinomas in the of forestomach, when rats were given diet containing 0.4 % caffeic acid for 2 years [35]. Despite this classification, CA is widely used in biomedical applications because of its excellent bioactive properties like anti-bacterial, anti-inflammatory and anti-oxidant [36]. In biomaterial based applications, factors like concentration, formulation, and release strategies can have an impact on the biocompatibility and potential toxicity of caffeic acid. For this reason, when investigating the potential applications of Caffeic acid in biomaterials, it is crucial to understand the implications of its classification.

3D Printing is an emerging technology to fabricate layer by layer scaffolds for applications in the field of tissue engineering [37,38] and drug delivery systems [39]. This technique is notable for its ability to create a varied range of materials using polymers and drugs by combining g-code and mechanical engineering technologies like multi-printing and printing inspection systems [40]. Therefore, it is a promising technique that could lead to the development of novel and adaptable specific scaffolds as an alternative to traditional treatments. These formulations would be characterized by their ability to mimic the mechanical properties of tissue, their precise structural and geometrical features, their ability to adjust drug concentrations, and their release profiles [41,42].

In this study, 3D printed scaffolds loaded with caffeic acid, based on PCL and PVP, were developed for use as wound dressings in drug delivery systems. The 3D printed scaffolds underwent various characterizations to assess their chemical, morphological, mechanical, and thermal properties. Additionally, drug release kinetics, swelling studies, and cell culture studies using NIH3T3 mouse fibroblasts were conducted to evaluate the biocompatibility and healing potential of 3D printed scaffolds. The novelty of this study lies in the use of caffeic acid in 3D printed scaffolds for wound dressing, in combination with PCL-PVP, marking its first application in tissue engineering.

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