Cellulose and its derivatives: towards biomedical applications

For biomedical applications, it is an essential requirement to assess the biocompatibility of materials and verify their interaction with cells, especially for applications where the material needs to remain in contact with living tissue and should not cause any cytotoxic or other side effects. Cellulose offers unique features of biodegradability, biocompatibility, low production cost as compared to synthetic biopolymers, abundance, sustainable resources, nontoxicity, and excellent mechanical properties. These features offer potential as bioresorbable polymers that plays an increasingly important role in biomedical applications due to their unique ability to be resorbed entirely in pre-designed time frames ranging from months to a few years.

Tissue engineering

Tissue engineering is known as an interdisciplinary field that applies the principles of engineering and life sciences toward the development of smart biological substitutes that potentially restore, maintain, and improve tissue functions that have malfunctioned (Table 6). The tissue engineering field generally utilizes biomaterials to develop constructs for intended medical interventions. Such constructs are to be exposed to living biological entities in the human body, from biomolecules and physiological fluids to cells, up to tissues and organs. In terms of physical properties, regenerative tissue material must possess optimal strength, e.g. compressive strength for bone tissue engineering, or tensile strength for artificial blood vessels and other soft tissue repairs. On the other hand, chemical considerations such as the surface chemistry of the materials are crucial, and the selection of materials must be rendered for specific application purposes. For instance, it is possible to tune porosity, thickness, and interconnectivity of nanocellulosic materials without compromising the mechanical properties for tissue scaffold production (Bäckdahl et al. 2008). For tissue engineering, cellulose as an additive or as primary scaffold material should have mechanical properties matching real tissues (Farzamfar et al. 2018; Hasan et al. 2018), promote porous structures for scaffolds (Hoo et al. 2013), or provide anchoring sites for osteoblasts (Gouma et al. 2012), and fibroblasts (Taokaew et al. 2015). The most commonly used cellulose derivatives for tissue engineering include cellulose acetate (Farzamfar et al. 2018), hydroxyethyl cellulose (Zulkifli et al. 2017), hydroxypropyl cellulose (Hoo et al. 2013), cellulose sulfate (Palaninathan et al. 2018), carboxymethyl cellulose (Hasan et al. 2018), methyl cellulose (Zhuo et al. 2017), and ethyl cellulose (Mao et al. 2018a).

Full size table

One of the ubiquitous usages of biomaterials in tissue engineering is in the production of a biologically compatible scaffold that will support the attachment, proliferation, and differentiation of living cells that contribute to the promotion of tissue regeneration in vitro and in vivo conditions. Mammalian cells are not able to attach to the cellulosic surfaces used in artificial tissue scaffolds due to their hydrophilic nature and low non-specific protein adsorption. However, cell adhesion to substrate surfaces in cellulosic materials can be improved by the addition of matrix ligands. For example, ionic charges can be added to the cellulose membranes to adsorb collagen on the membrane surfaces, which can promote cellular adhesion (Courtenay et al. 2017). The positively charged BC has been applied, in the absence of proteins, to enhance cell attachment (Courtenay et al. 2017). BC is a biomaterial with a huge potential in dental and oral applications (Canas-Gutierrez et al. 2020). Recently, cost-effective and user-friendly functional biopolymeric-based materials have been used as a promising tool for developing, repairing, and regenerating functional tissues and organs in the human body. The use of cellulosic composites has been proposed in developing scaffold constructs that can be implanted in patients to replace failing or malfunctioning organs. Moreover, the inclusion of the appropriate reinforcement material for tissue-engineered biocomposite scaffolds is a significant factor in improving its characteristics and sustained biocompatibility. The use of cellulosic materials as reinforcement in biocomposites is now a fast-growing field, on account of their property enhancing capabilities (Ao et al. 2017; Sajjad et al. 2019). For instance, cellulosic fibers have been demonstrated recently to improve the formidability of biocomposite scaffolds in bone tissue engineering applications due to their unique structure (Mao et al. 2018b). In addition, microfibrillated cellulose remarkably increases the surface area, and its interfibrillar hydrogen bonds facilitate network formation, which is desirable in bone tissue engineering (Ioniță et al. 2018). Moreover, CMC stimulates adhesion, spreading, and migration of mouse fibroblasts in vitro (Adachi et al. 1992; Aoshima and Jo 2013). Also, the presence of CMC decreases osteoclastogenesis by murine bone marrow progenitors (Agis et al. 2010), but increases osteoblast differentiation (Qi et al. 2018). Hydroxyethyl cellulose is a non-ionic, water-soluble polymer, and has a β-glucose linkage, which makes it a suitable candidate for tissue engineering applications. Hydroxyethyl cellulose increases cell viability and substantially stimulates cell growth (Tohamy et al. 2018). It also significantly enhances cell proliferation at high concentrations of hydroxyethyl cellulose (Chahal et al. 2016).

The appropriate mechanical properties of biomedical devices and materials are essential and very specific to the nature of the application area. For example, the elastic modulus of the material needs to be close to the medium and/or tissue that it is replacing or reinforcing. Nanocrystalline cellulose can be a promising material for cell attachment and proliferation due to its excellent mechanical properties and biocompatible nature. One particular advantage of using nanocrystalline cellulose is the fibrillar high aspect ratio building blocks, which construct a natural fiber network of fibrils or nanorods that is held together by hydrogen bonding and mechanical entanglement. Such a network could be even further reinforced mechanically by cross-linking the individual nanofibers. There are numerous cellular species cultured on nanocellulose biomaterials such as hydrogels, electrospun nanofibers, sponges, composites, and membranes (Luo et al. 2019). Among the sources of nanocellulose, bacterial nanocellulose is believed to be the most popular choice for cell culture due to its high porosity, biodegradability, and low toxicity (Halib et al. 2019). Usually, the rate of scaffold degradation under a given condition is an important issue as it should match the time of tissue formation to ensure the injured tissue is completely replaced by healthy tissue, and its function is restored.

Wound dressing

The wound healing process involves an elaborate series of biological phenomena to restore barrier functionality, prevent dehydration, and reduce the risk of bacterial infection. Burn wounds and skin grafting require the development of novel wound dressing materials. Cellulose-based polymers have a high potential for wound dressing applications (Table 6). As wound dressing material, they should promote water retention or high water absorption capacity (Wutticharoenmongkol et al. 2019) or promote porosity and dryness that abhors bacterial attachment (Henschen et al. 2016). Here, the cellulosic material must be shaped like a sheet and used as a cover on wounds. It is highly beneficial to make drug-loaded cellulose-based bandages (Fan et al. 2019). Nanocellulose has excellent potential for wound healing applications, based on its moisture absorption and water retention ability that can be implemented over the wound itself, to contribute towards lowering inflammatory responses and promoting fibroblast proliferation in the wound healing cascade (Wang et al. 2016). Nanofibrillar cellulose is an ideal matrix for wound healing due to its high surface area to volume ratio, high water-holding ability, and high porosity. Moreover, its structure allows to mimic the architecture of the extracellular matrix or tissue/organs. Nanofibrillar cellulose hydrogel is a novel material for controlling excessive wound contraction in vivo and in vitro (Nuutila et al. 2018). Nanofibrillar cellulosics such as CMC and CA are the most promising wound dressing cellulosic materials that have been used in the treatment of burns and ulcers due to biocompatibility with mucous membrane and skin, biodegradability, non-toxicity, low immunogenicity, high water bonding affinity, and swelling capacity (Gomaa et al. 2017; Hakkarainen et al. 2016). Oxidized cellulose nanofiber is also appropriate for wound healing applications because of its substantial water absorption capacity and well-dispersed cellulose fibrils (Shefa et al. 2017).

Using CMC in wound healing requires some modifications to decrease the consequent pain burden in patients. A low level of localized pain, postoperative bleeding, and synechia have been reported for dissolvable CMC foam dressing (Szczygielski et al. 2010). Dissolvable CMC foam can also be used as wound dressing after sinus surgery due to the observed low levels of postoperative bleeding and synechia formation during application (Szczygielski et al. 2010). Nanocomposites based on BC are prepared by the direct introduction of magnetic nanoparticles within the cellulose culture medium for efficient chronic wound healing. Bionanocomposites containing plant CNC have been reported to be suitable wound healing templates for accelerating tissue regeneration (Singla et al. 2017). CA is also a suitable candidate in biocomposites for wound healing scaffold upon developing electrospun nanofibers (Wutticharoenmongkol et al. 2019). Hydrophilicity and bioactivity of CA enables cellular interaction between CA and fibroblasts, which consequently promotes cell proliferation (Gomaa et al. 2017).

BC is an appealing candidate for wound healing applications based on its favorable characteristics, such as biocompatibility, nontoxicity, and mechanical stability. Furthermore, BC provides a moist environment for the wound, hence enhancing the healing process (Sulaeva et al. 2015; Zmejkoski et al. 2018). However, BCs provide a suitable environment on-site as wound dressing materials, but the pH conditions can affect their contribution to the healing process (Shao et al. 2015a). Different materials have been incorporated to develop BC-based biomaterials with enhanced properties to be suitable for wound dressing (Qiu et al. 2016). BC-montmorillonite-reinforced composites have been developed as wound dressing and regeneration materials for therapeutic applications without any side effects (Ul-Islam et al. 2013). BC-chitosan membranes show antibacterial activity and favorably low cytocompatibility for wound dressing (Lin et al. 2013). BC-based membranes show significant epithelialization and regeneration of the skin, faster than the commercial wound dressing product, Tegaderm™ (Lin et al. 2013). Besides, the BC membrane accelerates the wound healing process in a burn model system through the regulation of angiogenesis and connective tissue formation (Kwak et al. 2015). BC-based hydrogel microparticles have been used as a dressing material for coverage of partial-thickness burn wounds both in vitro and in vivo (Pandey et al. 2017). Oxidized BC is another kind of cellulosic materials, which is appropriate for wound healing since it possesses considerable water absorption capacity, antibacterial effect, and well-dispersed cellulose fibrils (Wu et al. 2018).

Drug delivery

A drug delivery system is defined as the release of drugs at an appropriate time, to specifically targeted organs in a specified amount. Drug delivery systems transfer drugs to the desired organs, tissues, or cells, where the transfer mechanism can be controlled to respond to environmental stimuli such as light, temperature, pH, chemical actions, and electric and magnetic fields. Cellulose has a long history of application in the pharmaceutical industry, where it has been used as a tablet-coating when blended with various excipients for oral administration. Despite an extended history of use in tableting, there is still ongoing research on the potential use of cellulose and its derivatives in advanced drug-loaded systems in terms of the rate of tablet dissolution as appropriate excipients or extended drug release as novel drug carriers (Table 6) (Abeer et al. 2014; Yan et al. 2019). As a drug delivery system, cellulosic materials should promote controllable diffusive properties and dissolvability. For instance, cellulose and its derivatives have been observed to exhibit definite drug delivery patterns by instant, controlled, or delayed-release in oral dosage forms (Godakanda et al. 2019; Jeddi and Mahkam 2019). Furthermore, the natural resistance of cellulosic materials to the acidic environment of the stomach makes them very practical to use as enteric coatings on capsules or tablets (Guo et al. 2002).

Extemporaneously, compounded medicines are used when a needed dose or dose form is commercially inaccessible, or when a particular dosing regime is required. Powdered cellulose and MCC are used as adsorbents, capsule diluents, and thickening stabilizing agents in compounded medicines (Marques-Marinho and Vianna-Soares 2013). MCC shows viscoelastic behavior and sensitivity to the strain rate. In high-speed tableting, the time for plastic deformation is limited, and hence, in this case, elastic effects are more significant (Roberts and Rowe 1985). Thus, in the formulation design and dosing, dependency of MCC to the strain rate should be considered (Thoorens et al. 2014).

CNFs possess a considerable potential in biomedicine as carrier for controlled drug delivery because of their suitable flexibility, conducive elasticity, low density, low toxicity, and relatively reactive surface, that can be used for grafting specific groups, in addition to being renewable and cheap. The rheological, barrier, and physicochemical characteristics of CNFs allow them to stabilize oil–water and air–water interfaces. Moreover, CNFs’ high surface area per unit mass provides stabilization of nanoparticles and a higher probability for positive molecular interaction with poorly soluble drugs. CNFs have been used as stabilizers for crystalline drug nanoparticles, as matrix former to obtain a long-lasting sustained drug release over several weeks, and as film former with immediate release properties for poorly soluble drug (Löbmann and Svagan 2017). CNFs can generally be converted into aerogel form during drug adsorption and subsequent freeze-drying (Bhandari et al. 2017). Plant-based CNFs have been successfully used as an injectable drug-releasing hydrogel in mice, demonstrating the potential application of CNFs as a matrix for controlled release or targeted local delivery of drug compounds in humans (Laurén et al. 2014).

CA nanofiber mats have been used mainly in diverse pharmaceutical applications due to their advantageous characteristics, like high shear strength and shear modulus, biocompatibility, regenerative properties, high affinity with other substances, biodegradability, and suitable flexural and tensile strength. In particular, CA-based drug-loaded nanofibers have received considerable attention in the development of topical and transdermal drug delivery systems (Yu et al. 2013). Besides, cellulose acetate phthalate is a novel material that provides the most efficient solution for pH-controlled drug release. One of the decisive applications of cellulose acetate phthalate is in microencapsulation, which is utilized in an aqueous or organic medium (Wan and Chui 1995). Cellulose acetate phthalate electrospun fibers facilitate resistance to HIV infections. These fibers, even after dissolution, are nontoxic for vaginal epithelial cells and vaginal lactobacilli. These fibers are suitable for loading anti-HIV drugs and in preventing HIV infection during sexual intercourse (Huang et al. 2012). Typically, microencapsulation with cellulose acetate phthalate has been done by coacervation phase separation, spray-drying, and extrusion methods (Wan and Chui 1995).

One of the most prevalent hydrophilic biodegradable polymers that has been used in controlled-release formulations and that has been approved by the United States Food and Drug Administration (FDA), is hydroxy propyl methyl cellulose (Hu et al. 2018). Injectable chitosan/glycerophosphate thermosensitive solutions containing vancomycin-loaded hydroxy propyl methyl cellulose microparticles are produced for the local treatment of osteomyelitis (Mahmoudian and Ganji 2017). The porous and spongy structure of a hydroxyl propyl methyl cellulose hydrogel allows for a long-term release profile in vitro, which provides excellent potential for usage in sustained antibiotic delivery (Mahmoudian and Ganji 2017).