This review summarizes the use of cellulose and polylactide for medical applications with particular emphasis on modern dressings. Although classic cotton and viscose dressings are still available and popular, the usefulness of new forms of cellulose (Cel) and its derivatives opens new wound treatment options. Therefore, trends in functionalizing traditional cellulose dressings, including products made of bacterial cellulose, and dressings from cellulose derivatives, are discussed. Polylactide (PLA), in turn, is a biodegradable and biocompatible polyester that fulfills plenty of tasks in many medical fields, from surgery to modern diagnostic methods. However, polylactide dressings can still be advantageous to the market. Thus, the next part of the article contains a recent update of available knowledge about PLA and its applications in regenerative medicine and drug-delivery systems. The last part is devoted to the possibilities of combining both materials in dressings and related problems and benefits. Methods for compatibilization with the surface of both polymers and new techniques for producing Cel/PLA composite materials are also described.
Cellulose dressings as a form of wound treatment are present in medical practice since antiquity. Ancient literature presents dressings as one of the stages of wound care (Nicoli Aldini et al. 2008). Textiles made of natural vegetable fibers, such as linen bandages, often soaked with therapeutic and antibacterial substances, were already used in ancient Egypt (Sipos et al. 2004; Thomas and Uzun 2019; Wilkins 1964). In the twentieth century, the development of plastics industry resulted in the introduction of synthetic fibers, in parallel with an increase of the wound-treating materials available, from classic woven, knitted and nonwoven dressings up to modern foams (Fogh and Nielsen 2015; Salisbury et al. 2022), hydrogels (Francesko et al. 2018; Shu et al. 2021; Wu et al. 2023; Zhang et al. 2019), hydrocolloids (Stoica et al. 2020b; Thomas 2008) and thin membranes (Gra?a et al. 2021). Composite dressings combine multiple functions in one product and their form varies depending on the raw materials used and the expected functionality (Gupta and Edwards 2019).
This work focuses on analyzing materials for modern products supporting regenerative medicine composed of cellulose and polylactide. It contains present-day state of knowledge about these two polymers and their combination for medical applications, however, with strong emphasis on wound dressings. It may also help with establishing whether polylactide/cellulose (PLA/Cel) systems have some unique advantages over these polymers acting alone. To understand their mutual interactions, many points are discussed, including structural, functional, and engineering issues. One of the biggest problems related to combining PLA and cellulose is their different affinity to water. Polylactide is hydrophobic and cellulose is hydrophilic, so the goal is to modify them in such way that will enhance interphase PLA/Cel interactions and improve mechanical properties of their composites.
Cellulose is the most classic and well-known natural polymer. From the earliest beginnings of wound healing, it has been present as a part of medical equipment and until this day it has not lost its great significance in the scientific world. As one can see, the versatility of cellulose applications has strongly increased with the material and chemical engineering development, although classical cotton fabrics are not forgotten in medicine and hospital environment (Gra?a et al. 2021). The aim of developing new solutions leads from the activation of medical products, which were previously passive like cotton gauzes and bandages (Gra?a et al. 2021; Lumbreras-Aguayo et al. 2019b), constructing cotton-reinforced modern forms of dressings (Lumbreras-Aguayo et al. 2019b), to pure nanoscale cellulose and its derivatives as healing materials (Alavi and Nokhodchi 2020; Cidreira et al. 2021; Liu et al. 2020). In addition, bacterial cellulose has also been considered as a smart material with some advantages over plant-based cellulose (Portela et al. 2019; Rathinamoorthy 2022).
In the face of a long history of cellulosic dressings, polylactide occurs as a quite new product, however, it has been known for years. Polylactide (PLA) is a biodegradable and biocompatible polymer (Basu et al. 2016; Gupta and Kumar 2007; Michalski et al. 2019) and is recognized as safe by the U.S. Food and Drug Administration. Therefore, PLA has attracted considerable attention as a candidate capable of replacing petroleum-based polymers due to its good processing and mechanical properties (Raquez et al. 2013). PLA is proposed for various applications in industrial, pharmaceutical, and environmental fields. Among these multiple fields of PLA utilization, biomedical usage is one of the most frequently proposed for PLA-based materials (Sinha Ray 2012).
It seems that both cellulose and polylactide as materials for medical applications can now have similar functionalities. However, traditional cellulose dressings still have a strong market position, also for economic reasons. Enriching them with a polylactide in active form, for example as a medium for drugs, could be a relatively cheap and effective way to modernize them and at the same time to meet the specific needs of patients. This can be the simplest way to launch PLA on the market, as the use of dressings in everyday life does not require medical consultation but they need to be affordable and easy to apply. The combination of both polymers in one material (for example via grafting or polymerization) may provide a possibility for new modifications, considering their different physical and chemical properties, the capability to perform different chemical reactions with other compounds, as well as the ability to degrade with all the consequences. Finally, it is worth examining whether the characteristics of the PLA/Cel systems are a simple sum of the features of their components or, on the contrary, the ingredients complement each other, presenting an improved quality, not available when they perform separately.
The main building block of a cotton fiber is cellulose, whose quality and structure determine its most important properties. Cotton has the highest content of cellulose from all-natural sources, reaching up to 96% dry matter (Segal and Wakelyn 1985), followed by sisal and pineapple leaf fibers (Gassan et al. 2001). Cellulose, a polysaccharide with a summary formula (C6H10O5)n, is a large molecular structure polymer resulting from a natural polycondensation. The cellulose macromolecule chain is made of β-d-glucopyranosyl units connected with 1,4-β-glycosidic bonds. The repeated unit is the glucose residue (French 2017).The non-reducing end of a cellulose chain is composed of a hydroxyl group, whereas the reducing end is a hemiacetal. The presence of hydroxyl groups in the molecule determines the reactivity of cellulose, although these groups, due to the location in the spatial structure, are not just as reactive. The most reactive group is the one located at C2, then with C6 carbon. Hydroxyl groups, as they are characterized by polarity, form hydrogen bonds between macromolecules, which in turn causes stiffening of the chain and the formation of strongly ordered spatial structures—the so-called crystalline phase in fiber.
To describe the properties of the cellulose polymer, specify such features as:
average polymerization degree;
average degree of crystallinity;
construction of the elementary cell in the crystalline phase.
High dispersity of molar mass is a typical feature of cellulose isolated from natural sources. Native cellulose consists of macromolecules with different polymerization degrees, while the average polymerization degree is different for cellulose materials of different origins (e.g., for cotton cellulose and cellulose from wood). Similar diversity can be observed in the degree of crystallinity. Various sources give the following value: according to Urbańczyk (1985), the degree of crystallinity in cellulose derived from plant fibers reaches 60–80%; according to "Handbook of Polymers", it is 75% for cotton (which is the cleanest source of cellulose I), while according to "Comprehensive Cellulose Chemistry" it is about 60%, with this applying to cotton fibers undergoing initial physicochemical treatment (Klemm et al. 1998). However, as in the case of all cellulosic materials, crystallinity values have considerable dependence on the exact methods, even just considering X-ray diffraction (French 2020).
A crystal’s unit cell is the smallest unit of the crystal that can be used figuratively to construct the structure of the crystal by simple repetition of the unit cell along the X, Y, and Z axes of the crystal. The six basic parameters are in the XYZ axis system of the lattice, (a, b, c)—the distances at which the cell elements are repeated, and the angles between the axles (α, β, γ). However, the Miller indicators (h, k, l) define crystallographic planes that result in the various peaks of photon intensity on a diffraction pattern. These characteristics are different for every polymorph (French 2014). Chemical and physicochemical treatment has a significant impact on the form of an elementary cell, a crystallographic variety, as well as the content of crystalline material in fiber. An example would be the mercerization process, where under specific conditions native cellulose I is converted to cellulose II, whose parameters of the structure of the elementary cell of crystalline differ from the output material (Takahashi and Takenaka 1987). A different shape of the elementary cell carries, therefore, a change in physical and chemical parameters, such as changing the density of the material, differences in mechanical properties, as well as the ability to bind dyes. Other polymorphic forms of cellulose are cellulose III, which can be obtained as a result of ammonia swelling cellulose I or II, and cellulose IV, an effect of force and heat to other cellulose varieties (Klemm et al. 1998). The degree of cellulose crystallinity changes with the origin of the material and the processing it was subjected to, moreover, the properties of converted polymorphs depend on their parental structures (Wada et al. 2004). A different question is whether these conversions are reversible. Hindi (2016) lists seven interconvertible polymorphs of cellulose, namely, Iα, Iβ II, IIII, IIIII, IVI, and IVII and states that celluloses IIII and IIIII revert to their previous forms in a high temperature and humid environment. The reversion is possible also in the case of cellulose IV.
Although cellulose II is typically the result of mercerization with NaOH or dissolution and regeneration as in the viscose or NMMO processes for making rayon or lyocell, its natural sources are known. This material occurs in the sea algae from Halicystis species, under certain rare conditions. Mutant bacteria have also produced cellulose II. The bacterial cellulose in the form of cellulose II is most often produced by the strain of Gluconacetobacter xylinus (Dufresne 2017). However, the typical bacterial and algal cellulose is cellulose I, and more precisely Iα (Picheth et al. 2017; Rusdi et al. 2022; Wada et al. 2001), whereas, as the research on Acetobacter xylinum ATCC23769 indicated, the crystallographic structure of cellulose (I or II) can be modified the culture conditions (Hirai et al. 1997). Other bacteria strains used for cellulose production are Agrobacterium, and Sarcina. The quality of bacterial cellulose can be diversified by controlling nutrient sources (meaning carbon sources) and culture conditions of bacteria strains (Abeer et al. 2014; Gullo et al. 2017). The influence of pH, temperature, and access to UV light was studied by Lazarini et al. (2018) on the Gluconacetobacter hansenii. The G. hansenii variants grown under different pH and UV conditions showed lower capacity to BC production when compared to original G. hansenii ATCC 23769 (Lazarini et al. 2018). In the review of bacterial cellulose for wound healing applications (Ahmed et al. 2020), BC in general is characterized by greater purity, the ability to absorb water, and porosity (Table 1). The authors discuss also mechanical properties of BC, and its Young’s modulus and tensile strength which are comparable to aramid fibers, and indicate it as a reinforcement in composites. Moreover, BC is a promising medical material that does not require initial, time-consuming and expensive purification. Naomi et al. (2020) describes bacterial and plant cellulose in detail. According to that work, the main BC differences compared to vegetable cellulose are:
1.
Purity of the material (without the presence of hemicellulose, lignin, waxes, and other impurities).
2.
Mechanical properties (Young’s modulus, tensile strength) beneficial for tissue scaffolding structure, e.g. bone tissue (Torgbo and Sukyai 2018)
3.
The higher degree of crystallinity (over 80%) (Revin et al. 2021).
4.
High water absorption, but relatively low Water Vapor Transmission Rate.
5.
No immune response, no inflammatory reaction after contact with live tissue.
6.
Ease of shaping due to the high flexibility module.
7.
Much higher porosity, as well as a larger size of pores.
8.
Higher hydrophilicity.
Table 1 Parameters of bacterial cellulose, plant cellulose and PLA nanofibers. Details on PLA enantiomers have been already shown (Brzeziński and Biela 2014)
However, these differences, especially mechanical properties and water absorption, depend on production medium composition, for example the concentration of sugar. As reported, BC from sago liquid waste showed a tensile strength of 44.2–87.3?MPa, Young’s Modulus of 0.86–1.64 GPa and water holding capacity of 85.9–98.6?g?g?1. It could also be observed that the increased mechanical strength is linked to lower water holding capacity (Yanti et al. 2021). It is also worth mentioning that mechanical modifications influence BC properties as well as cultivation methods (Betlej et al. 2021). As one can see, many factors affecting the final form of BC determine its versatility for various applications. Usefulness for therapeutic purposes and biocompatibility with human tissues, however, seems to be at a similar level as plant cellulose—the effectiveness of improving processes of regeneration, cell adhesion and hemostatic effects depend mainly on the modifications and the presence of additional medicinal compounds. Some authors, nevertheless, emphasize that its natural structure also closely mimics many biological tissue properties (e.g. collagen fibers of bone and skin tissue), it has an ability to regulate cell adhesion, and its antigen immobilization capability for biosensor applications (Abazari et al. 2021).
Currently, bacterial cellulose is used in various aspects of regenerative medicine, from wound treatment, through the use of drug delivery systems, to tissue reconstruction (Table 2). BC occurs in various forms, both on a micro and nanoscale—as membranes, fibers (and materials made of them, usually nonwoven), hydrogels and composites. A commercial example is Dermafill? (previously known as Biofill?) membrane dressing that acts as a temporary skin substitute (Castro et al. 1988), but there are more products on the market and even more solutions under research, proving usefulness of this material (Zhong 2020).
Table 2 Areas of BC application in regenerative medicine
Fibrous dressings, regardless of the type of fibers found in them (both natural and artificial/synthetic) are manufactured in the woven and non-woven form. Structures such as cotton wool were made use of relatively late (compared to the world history of wound dressings)—around 200?years ago. Cotton wool consisted of washed, loose and combed cotton fibers. Therefore, it was supposed to replace the traditional linen ripped strips or unraveled threads made of old clothing (Elliott 1957).
Although the last few dozen years have allowed for the development of advanced technologies of dressings supporting wound treatment, still the most typical and widely available cellulose dressing is gauze, bleached fabric, loosely woven with canvas weave. Initially, it was produced only from natural cotton fibers, but currently on the market there are also gauzes made of artificial cellulose fibers or cotton/viscose mix. Gauze dressings only fulfill basic tasks, like protecting the wound against the external environment and absorbing exudate. Their properties are determined by the number of warp threads- the greater the number, the more the dressing absorbs. A sufficiently strong twist of yarn and other parameters of spinning are also important to prevent the dressing from being undesirably distributed when removing it from the wound. Gauze as a compress absorbs blood and bodily fluids. While in the form of a bandage, it is also used as a secondary dressing, holding and covering the primary (or, in other words, active) dressing, which has therapeutic properties and needs to be secured from moving and/or from external environment. An example of primary dressing that is combined with topical cover is non-adherent HELIX3-CM? Collagen Matrix, suitable for burns, sores, blisters, ulcers, and wounds. Simplicity and the relatively low cost of the production of the standard gauze, as well as the ease of adapting to the patient's specific needs, mean that its high popularity will probably last long.
An interesting attempt to enrich the functionality of gauze to a wide extent was presented by Said (2021). The designed gauze was first pre-modified by chitosan cationization or anionic carboxymethylation. Then, by successively applying hydroxyapatite, silver nanoparticles and ginger oil, it gained anti-inflammatory, antimicrobial and anti-UV properties. Another strategy was to modify the surface of the gauze by grafting the poly(Methacrylic Acid) (PMAA), which was followed by testing the implementation of ZnO nanoparticles to obtain the antibacterial and antimicrobial functions and by investigation of the drug releasing profile after loading it with nalidixic acid. Compared to an unmodified gauze, the antibacterial effect was the result of PMAA grafting itself. The results were due to bactericidal properties of acrylic acid polymers. The explanation is that acidic environment disturbs cytoplasmic homeostasis pH, while acid groups reduce bacterial adhesion. However, 100% inhibition effect for S. epidermidis bacteria was achieved only by adding ZnO (Lumbreras-Aguayo et al. 2019a). The process of hemostasis is to be supported by gauze with grafted carboxymethyl chitosan and covered with gelatin and alginate using the Layer-By-Layer method, a technique of fabrication of thin films made by depositing respectively oppositely-charged materials (Zheng et al. 2021). A relatively simple way to improve functionality is to use cotton gauze, present on the market (classic and covered with anti-adhesive wax) to apply 2-deoxy-D-ribose (2dDR) which would support angiogenesis (Andleeb et al. 2020). In the case of a hydrophobic wax dressing, it was necessary to construct a carrier using paraffin, ethanol, and poly(ethylene glycol) (PEG) in various configurations or implement 2dDR in a partly diluted wax cover. Another way of modifying conventional cotton fabric was grafting L-cysteine (Cys) on the surface and then implementing copper nanoparticles in the presence of citric acid. Such material exhibited satisfactory activity against bacteria S. aureus and E. coli and excellent washing fastness (Qingbo Xu et al. 2018a, b).
In recent years, the greige cotton, which is unbleached cotton as a dressing material conducive to hemostatic processes in open wounds, has become the object of wider interest. In the work of Edwards et al. (2022), it occurred that highly cleaned and sterile unbleached cotton, due to its constituents, may produce hydrogen peroxide at a certain level. Moreover, it can be modulated with ascorbic acid by impregnation with classical pad-dry method, resulting in antimicrobial properties. It is beneficial from the ecological and economic point of view to omit the cotton bleaching stage and avoid the use of chemicals necessary for this process (such as wetting agents, and whitening agents based on hydrogen peroxide or chlorine compounds). It is worth emphasizing that naturally occurring substances remain on the fibers—pectins, proteins, waxes, hemicellulose, fats, as well as vestigial amounts of inorganic compounds called ash. Leaving them on the fiber affects the hydrophobicity and polarity of the surface and creates an environment conducive to blood clotting. On the other hand, dressings consisting only of greige cotton may not absorb exudate sufficiently for exactly the same reasons (Vincent Edwards et al. 2020).
Apart from cotton, attempts are made to adapt other natural cellulose fibers to the needs of wound treatment. As in the case of greige cotton, cellulose material with a natural addition of specific substances supporting treatment is linen (Linum L.). Recent research shows that linen dressings have healing effects on wounds not only because of cellulose material and polymers naturally occurring with it (hemicellulose, lignin, pectin), but also because of the presence of potentially bioactive substances, such as vanillin, 4-hydroxybenzoic acid, ferulic acid, coumaric acid, syringaldehyde, olyhydroxybutyrate/hydroxybutyrate, and polyamines. By examination on cellular line of mouse BALB/3T3 fibroblasts and normal human dermal fibroblast (NHDF), and normal human epidermal keratinocytes (NHEK) line, human dermal microvascular endothelial (HMVEC) cell line, epidermal carcinoma cancer A431, and monocyte THP-1 cell line, it has been shown that genetically modified linen fibers, differing from unmodified fibers with increased content of the above-mentioned compounds, accelerated the proliferative activity of damaged tissues (G?barowski et al. 2020).
The presence of hydroxyl groups in cellulose macromolecules results in high reactivity of the polymer and great possibilities for modification for medical purposes. Typical reactions with OH groups are etherification, esterification, acetalization, and oxidation. Some of the obtained derivatives (especially esters and ethers) are well known and have been produced commercially for a long time (Klemm et al. 1999).
In an overview of cellulose and its derivatives for wound healing, Tudoroiu mentions: cellulose esters, cellulose acetate (CA), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimelitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Among ethers, there are sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HEC), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose (HEMC), and benzylcellulose. They appear also in combinations of two or more and usually contain active pharmaceutical ingredients (Tudoroiu et al. 2021). Usually, most reports also mention bacterial cellulose, although its production is significantly different.
Cellulose derivatives due to their specific properties influencing the easy forming of various forms of dressing and healing process (alone or with other components) are versatile and flexible materials. The main advantage over pure cellulose is improved solubility in water with some exception of, for example, ethylcellulose or cellulose acetate. Moreover, the properties of cellulose-based nanoparticles can prolong circulation of drug carriers in organism by increasing drug solubility and stability and thus enhance their bioavailability, or perform as biosensors and as a tool of targeted therapy thanks to easy customization for specific tasks (Hosny et al. 2022). Biosensors based on oxidized or carboxylated cellulose nanomaterials promote amide linkage between amide groups of proteins and nucleic acids, and carboxyl groups grafted onto cellulose molecules which increases their resistance to external environment (Teodoro et al. 2021). As biosensors, they might be useful for detection of such bio-molecules as urea, lactate, glucose, genes, amino acids, cholesterol, and proteins (Kamel and Khattab 2020). Cellulose derivatives, in particular carboxymethyl cellulose (CMC), cellulose acetate and bacterial cellulose were also discussed from a clinical point of view. Some advantages are as follows:
1.
cellulose acetate—excellent scaffolding biomaterial for implementation of drugs and other compounds with anti-microbial, antioxidant, anti-inflammatory, and antiviral activity
2.
carboxymethyl cellulose—the ability to construct hydrogels in the presence of metallic ions,
3.
bacterial cellulose – highly effective surface area, and a hydrophilic nature that gives it a high liquid loading capacity, ability to drug carrying, good mechanical properties and breathability (Abazari et al. 2021)
In recent years, (CMC)-based wound dressing materials have been strongly discussed due to their biocompatibility, biodegradability, low cost, and other properties such as tissue resembling and non-toxicity (Kanikireddy et al. 2020). Various forms and practical use of dressings are possible (Fig.?1).
Fig. 1
CMC-based dressings. Reprinted from (Kanikireddy et al. 2020) with permission from Elsevier
Some CMC dressings are already present on the market, such as Aquacel?, which was proven to encapsulate potentially pathogenic bacteria in its gel structure when it covers the wound (Walker et al. 2003). The basic Aquacel? is composed only of sodium carboxymethylcellulose spun into fibers and then shaped into dressing form. Put into the wound, it absorbs exudation inside of the fibers, keeping it away from the tissue. At the same time, it changes the structure to the gel and maintains the moist wound environment for optimal healing (Williams 1999). Attempts were made to use cotton cellulose from waste remaining after production processes to produce CMC and create hydrogel wound dressing. Recovered cotton fibers were cut and pretreated with 20% sodium hydroxide solution to remove impurities, and then bleached in 6% solution of sodium hypochlorite. In the next step, CMC was synthesized by the etherification with various amounts of sodium monochloroacetate (SMCA). Hydrogel was obtained through the cross-linking reaction in the presence of epichlorohydrin (ECH). Different combinations of cellulose and CMC were used to achieve desired results- suitable exudate absorption, wound dehydration, and tissue regeneration environment (Jirawitchalert et al. 2022).
Hydroxypropyl cellulose (HPC) was a matrix for nanocomposite films enriched with graphene oxide (GO) grafted silver-coated zinc oxide nanoparticles (Ag/ZnO) (Fig.?2). These so-called AGO nanofillers positively influenced mechanical strength, UV resistance, and antibacterial performance (Wang et al. 2019a, b). Another solution for antibacterial properties was Polyhexamethylene guanidine hydrochloride (PHMG) grafted to cellulose diacetate (CDA) wound dressing surface through an amide reaction. The dressing had a nanofibrous structure made by electrospinning, which additionally enhanced hydrophilicity. Such prepared materials were tested for water absorption, and absorbing capacity (or, in different words, water holding capacity). In the first case, the weight of samples soaked with saline solution for 10?s was compared to the weight of lyophilized ones. Secondly, the weight of samples previously immersed in saline overnight was measured to determine water retention over a certain period of time. Results showed that increasing amount of PHMG has significantly influenced all those parameters (Xiao et al. 2022). Cellulose diacetate wound dressing also supports hemostasis and counteracts excessive blood loss (Liang et al. 2021).
Fig. 2
Copyright 2019 American Chemical Society
Synthetic Route for AGO/hydroxypropyl cellulose nanocomposite films. Reprinted with permission from (Wang et al. 2019a, b), source.
Hydroxypropyl methylcellulose (HPMC) combined with collagen enriched with povidone-iodine and formed into scaffolds effectively facilitated the proliferation of fibroblast cells with no toxic effects (Kesavan et al. 2022). A combination of ethylcellulose/hydroxypropyl methylcellulose nanofibers was loaded with aloe vera extract and formed into a wound healing dressing mat, which exhibited enhanced cell proliferation, adhesion, and antibacterial activity (Mohebian et al. 2022).
Abstract
Introduction
The structure and properties of cellulose
Polylactide
PLA as matrix for drug delivery systems, a recent update
PLA/Cel systems
Conclusions
Availability of data and materials
Abbreviations
References
Acknowledgments
Author information
Ethics declarations
#####
In this part of the review, the focus will be on the application of PLA-based materials for regenerative medicine and drug delivery systems. Since there are numerous reviews about PLA-based materials in drug delivery, describing PLA safety (Pawar et al. 2014; Ramot et al. 2016) and biomedical applications of its copolymers (Bawa and Oh 2017; Jain et al. 2016; Oh 2011), stereocomplexes (Bertin 2012; Brzeziński and Biela 2015; Tsuji 2016), hydrogels (Basu et al. 2016), and nanoparticles (NPs) (Casalini et al. 2019; Kumari et al. 2010; Tyler et al. 2016). Moreover, the clinical applications of PLA were also summarized (DeStefano et al. 2020). There are also some examples of PLA-based NPs under clinical trials (Niza et al. 2021; Prabhu et al. 2015), for instance, Genexol-PM or BIND-014?. Therefore, this part presents only recent achievements in this field which were published last or this year. However, there is also intention to outline wider use of polylactide in form of fibers, its modifications and perspectives.
Polylactide (PLA) is a biocompatible polyester that can be obtained by polycondensation of lactic acid or the ring-opening polymerization (ROP) of lactide. (Slomkowski et al. 2014). The building block of PLA can be composed both from optically active l- and d-enantiomers. Therefore, pure poly-l-lactic acid (PLLA) or poly-d-lactic acid (PDLA) can be produced from l-lactic and d-lactic acid, respectively (Zibiao Li et al. 2016). Moreover, the polymerization of a racemic mixture of both enantiomers leads to the preparation of poly-d,l-lactic acid (PDLLA). The structure of the PLA chain determines the properties of the resulting macromolecule and, as consequence, PLLA/PDLA are semi-crystalline polymers whereas the PDLLA is an amorphous polymer. In addition, the equimolar mixture of PLLA and PDLA forms a supramolecular complex which is called stereocomplex (Tsuji 2005). The formation of this complex improves the mechanical and thermal resistance for degradation of PLA-based materials (Zibiao Li et al. 2016).
The PLAs are typically obtained via polycondensation or polymerization (Slomkowski et al. 2014). The first method uses the reaction between hydroxyl and carboxyl groups of lactic acid to form ester bonds and obtain the desired polymer (Cheng et al. 2009). The ring-opening polymerization (ROP) of lactide (cyclic dimer of lactic acid) is the most popular method for PLA synthesis because it allows for the preparation of high molecular weight polymers with the absence of the side products typically observed during polycondesation. Moreover, the stannous octoate (Sn(Oct)2) as catalyst and alcohol as initiator are used for the PLA synthesis (Kowalski et al. 2000). However, various new catalysts both for coordination, cationic, and organocatalyzed polymerization were recently proposed (Kamber et al. 2007; Mezzasalma et al. 2017; Sebai et al. 2018). In addition, the star-shaped, hyper-branched, and dendritic PLAs can be prepared from the appropriate initiators of LA polymerization (Bednarek 2016; Michalski et al. 2019).
Research on the use of polylactide in medicine, including regenerative medicine, has been conducted with high intensity for several decades (Li et al. 2020). At the end of the twentieth century, Bendix (1998) presented an application for PLA and its copolymers (such as glycolide, trimethylene carbonate, and caprolactone) mainly in the form of screws, pins (which means surgical accessories intended for bone fixation), plates in surgery and orthopedics (homopolymers, PDLLA, L- and d,l-lactide copolymers), chopped drug release systems, surgical thread components and other medical textile materials (PLA and its copolymers with glycolide and TMC). Currently, the scope of polylactide applications has expanded significantly. As reported in 2016, Tyler (2016) mentions such fields of medicine as:
Orthopedics (bone regeneration, resorbable screws),
Neurology (peripheral nerves, spinal cord),
Cardiology (stents),
Dentistry (tissue regeneration, fillers),
General and plastic surgery (hernial nets, surgical threads, lifting threads, fillers),
Gynecology (stabilizing nets),
Radiology (theranostic imaging),
oncology (drug delivery systems, vaccines).
Until recently, polyesters (both aromatic and aliphatic) were not the main component of broadly understood dressings but were used as a strengthening add-on. An example is the Silflex? dressing made of a polyester mesh, whose functionality is based on the outer, coating silicone layer. There are already dressings on the market with polylactide. Suprathel? is a flexible and permeable to gases and liquid membrane, with such components as polylactide, trimethylene carbonate, and ε-caprolactone. Suprathel? is intended for treating burns, and thanks to the ability to biodegradate, it avoids painful changes of the dressing because it degrades directly in the wound. The conducted research among patients suffering from chronic wounds associated with diabetes (for example diabetic foot) also indicated its effectiveness in reducing the size of treated chronic wounds, at the same level as in the case of non-diabetic wounds (Nischwitz et al. 2021). The positive effect of polylactide on wounds is also confirmed by other studies in which nanofibrous polylactide nonwovens were subjected to tests on the porcine model (Menclová et al. 2021a, b). It has also been shown in vivo that PLA product strengthened the proliferative phase in the treatment of wounds compared to chitosan fabrics of similar structure (Menclová et al. 2021a, b). This shows that in the case of dressing materials, polylactide is still a relatively new material and the possibilities of the use of polylactide dressing materials are still to be learned and require further research.
Attempts are being made to modify its properties without the participation of additional substances, for example by plasma. In the 2015 examination, two types of non-woven fabrics, spun-bonded and needle-punched, both made of D-lactide, were put under the low-temperature plasma. The action of plasma was tested in two variants, in the presence of atmospheric air and C6F14 (perfluorohexane). The operation of the plasma from the air has increased the sorption properties of polylactide fibers, which according to the authors of the study predestines the received material for the category of superabsorbents. In turn, as a result of plasma treatment, perfluorohexane increased its hydrophobicity. The disadvantage of modification may be its impermanence, because the changes in the surface activity of the fibers disappeared after a few months (Urbaniak-Domagala et al. 2016).
The subject of interest is polylactide and its copolymers, most often in the form of nanofibers produced by the electrospinning method (Kanmaz et al. 2018). Nanofibers, due to the specific dimensions and significant advantage of the surface above the volume, are materials with increased surface activity affecting interactions in the treated area and can imitate the properties of external cell matrix (Extracellular Matrix, ECM), in particular, peptide and hyaluronic acid nanofibers (Mohiti-Asli and Loboa 2016).
Polylactide nonwovens can be modified for special applications already at the production stage, through production parameters, or by changing the parameters of the spinning solution, including the addition of active substances and drugs. Several factors influence the final form and functionality (Sharifi et al. 2020; Antoniya Toncheva et al. 2014). Production parameters determine the physical, thermal, and mechanical properties of fibers, while the additives primarily give medicinal, antiseptic, and antibacterial properties, although above a certain concentration production also requires adaptation of spinning conditions due to the impact on the properties of a spinning solution (by changing viscosity, the presence of dispersion agents). The form of fibers, porosity, and transverse dimensions are also affected by the presence of copolymers. It is also known that copolymers affect the effectiveness of dressings. It has been shown in in vitro and in vivo research that the membrane from the polylactide/poly(vinyl alcohol)/sodium alginate (PLA/PVA/SA) mix improves fibroblast proliferation and reduces the inflammatory response at an early stage of healing compared to membranes of pure PLA, while the effect of collagen deposition is clearer in the case of the latter (Bi et al. 2020). However, the effectiveness of releasing drugs is influenced by the crystallinity of the polymer due to the difficult access of water molecules to the crystalline phase. The use of nanofibers with active medical compounds for the treatment of wounds is already the subject of several studies (Ambekar and Kandasubramanian 2019; Arida et al. 2021; Liu et al. 2017). Typical active additives for the spinning solution used in various combinations are natural extracts, metal nanoparticles, peptides, antibiotics, growth factors, both in molecular form and encapsulated, or mixture of copolymers and it is summarized in Table 3.
Table 3 Recent examples of fibrous PLA materials for wound dressings and tissue regeneration
The polylactide products, such as nanofibers, foams, and films, regardless of whether they have been enriched in the production process, undergo further modifications. In tissue engineering, the change in surface properties is often aimed at increasing an affinity to the human tissues. Cells' adhesion is influenced by the polymer surface wettability, free surface energy, surface charge (an electric charge present on the surface of the material), as well as the chemical structure of the outer layer and its morphology. Generally, highly adhesive tissue material is hydrophilic with a surface charge with the opposite charge to the surface of the cells. Specific needs determine the values of the above parameters (Wang et al. 2005). However, it is worth mentioning that some results show that the cells are able to adhere and proliferate either on hydrophilic and hydrophobic surfaces, although the number of cells on hydrophobic surface initially decreases to finally increase after time (Ishizaki et al. 2010). Another research on superhydrophobic materials and their interactions with proteins and cells highlights the importance of surface topology in protein and cell adhesion (Louren?o et al. 2012). In this study, protein adsorption was higher on smooth surfaces than textured. The relationship between cell adhesion and surface roughness was also relevant, as cell adhesion and proliferation were inhibited on rough surfaces; however, cells remained viable and active. This means that good tissue affinity is a complex phenomenon and cannot be easily determined (Ferrari et al. 2019). Increasing the hydrophilicity of polylactide products is the subject of great interest. It is usually achieved with physical and chemical methods, through γ-ray irradiation (Qi et al. 2019), surface hydrolysis (Lee and Yeo 2016; Liu et al. 2019; Tham et al. 2014), plasma or laser treatment (Kudryavtseva et al. 2017; Mohsenimehr et al. 2020; Rytlewski et al. 2012; Stoleru et al. 2016; Wan et al. 2004), and the choice of the method also affects other surface properties such as roughness (surface morphology) or cell affinity. Plasma is the most versatile method and its impact causes various interactions with the material: cleaning, etching, activation by creating functional groups, grafting, and polymerization (Cools et al. 2014). At the stage of spinning the fibers, admixtures of hydrophilic copolymers, including poly(ethylene glycol), are used in the spinning solution (Hendrick and Frey 2014; Suzuki et al. 2018). In the wetting tests (by contact angle measurement), it has been shown that the value of the wetting angle decreases proportionally as the PEG percentage in the mixture increases (Athanasoulia et al. 2019; Athanasoulia and Tarantili 2017). Another solution is to impregnate polylactide material with poly(ethylene glycol) copolymers. PDLLA membranes saturated with an amphiphilic monomethoxyl poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PDLLA) showed changes in the wetting angle from 74.5° to 50°, depending on the solution concentration (Yang et al. 2018). The PEG connection method to PLA (mixing or grafting to the surface) is important from the point of view of the mechanical properties and parameters of the spinning solution, because the PEG add-on causes a reduction of the strength of the mixture and increases the viscosity of the spinning solution (Kruse et al. 2018; Toncheva et al. 2016). Zhu modified films from high molecular weight poly-l-lactide by immersing them with poly-d-lactide with low molecular weight and poly (d-lactic acid-co-glucose) copolymer (PDLAG) dissolved in chloroform (Zhu et al. 2021). The submersion in a solution for more than 3?min resulted in swelling of the foil, and in a further step its destabilization. As a result, stereocomplexed crystals are formed on the surface of the foil, and homogeneous crystals inside the foil, and hydrophilicity improved because of the presence of glucose. The next method of connecting the PEG hydrophilic groups is to create a three-element structure (scaffolding), in which the PLA-b-PEG block copolymer is a kind of "glue" bonding with a hydrophobic PLA and hydrophilic PEG. The dissolved mixture was slowly poured into the powdered NaCl which then, after the polymer's solving and thermal recrystallization, was washed out and thus obtained a porous scaffolding structure (Zhu et al. 2015).
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