Emerging Biofabrication Techniques: A Review on Natural Polymers for Biomedical Applications

Natural polymers have been widely used for biomedical applications in recent decades. They offer the advantages of resembling the extracellular matrix of native tissues and retaining biochemical cues and properties necessary to enhance their biocompatibility, so they usually improve the cellular attachment and behavior and avoid immunological reactions. Moreover, they offer a rapid degradability through natural enzymatic or chemical processes. However, natural polymers present poor mechanical strength, which frequently makes the manipulation processes difficult. Recent advances in biofabrication, 3D printing, microfluidics, and cell-electrospinning allow the manufacturing of complex natural polymer matrixes with biophysical and structural properties similar to those of the extracellular matrix. In addition, these techniques offer the possibility of incorporating different cell lines into the fabrication process, a revolutionary strategy broadly explored in recent years to produce cell-laden scaffolds that can better mimic the properties of functional tissues. In this review, the use of 3D printing, microfluidics, and electrospinning approaches has been extensively investigated for the biofabrication of naturally derived polymer scaffolds with encapsulated cells intended for biomedical applications (e.g., cell therapies, bone and dental grafts, cardiovascular or musculoskeletal tissue regeneration, and wound healing).

Puertas-Bartolomé, M., Mora-Boza, A. & García-Fernández, L. Emerging Biofabrication Techniques: A Review on Natural Polymers for Biomedical Applications. Polymers 13, 1209 (2021). Cite

Characterization Techniques for Emulsion-Based Antioxidant Carriers with Biomedical Applications

Emulsion-based antioxidant carriers are widely used in the food industry and pharmacology. After designing and synthesizing a determined emulsion-based antioxidant vehicle, it is essential to physicochemically characterize it in order to check if it meets the expected requirements for each application. In this sense, a good understanding of the basis of characterization techniques and methods to evaluate the design and performance of these encapsulation systems is crucial. In this chapter, the main characterization techniques of emulsion-based antioxidant carriers for biomedical applications are presented. A wide variety of techniques used in the evaluation of both continuous and dispersed phases of the emulsion system have been reviewed, from stability, rheology, cytotoxicity or sterilization of the whole emulsion; to the specific study of properties such as morphology, structure or size of the dispersed phase. Special emphasis has been placed on the antioxidant activity of the carriers being the key advantage of these emulsion-based systems.

Pontes-Quero, G. M. et al. Characterization Techniques for Emulsion-Based Antioxidant Carriers with Biomedical Applications. in Emulsion‐based Encapsulation of Antioxidants: Design and Performance (ed. Aboudzadeh, M. A.) 423–462 (Springer International Publishing, 2020). doi:10.1007/978-3-030-62052-3_12. Cite

Modulation of Inflammatory Mediators by Polymeric Nanoparticles Loaded with Anti-Inflammatory Drugs

The first-line treatment of osteoarthritis is based on anti-inflammatory drugs, the most currently used being nonsteroidal anti-inflammatory drugs, selective cyclooxygenase 2 (COX-2) inhibitors and corticoids. Most of them present cytotoxicity and low bioavailabil-ity in physiological conditions, making necessary the administration of high drug con-centrations causing several side effects. The goal of this work was to encapsulate three hydrophobic anti-inflammatory drugs of different natures (celecoxib, tenoxicam and dexamethasone) into core-shell terpolymer nanoparticles with potential applications in osteoarthritis. Nanoparticles presented hydrodynamic diameters between 110 and 130 nm and almost neutral surface charges (between −1 and −5 mV). Encapsulation efficien-cies were highly dependent on the loaded drug and its water solubility, having higher values for celecoxib (39–72%) followed by tenoxicam (20–24%) and dexamethasone (14–26%). Nanoencapsulation reduced celecoxib and dexamethasone cytotoxicity in human articular chondrocytes and murine RAW264.7 macrophages. Moreover, the three loaded systems did not show cytotoxic effects in a wide range of concentrations. Celecoxib and dexamethasone-loaded nanoparticles reduced the release of different inflammatory medi-ators (NO, TNF-α, IL-1β, IL-6, PGE2 and IL-10) by lipopolysaccharide (LPS)-stimulated RAW264.7. Tenoxicam-loaded nanoparticles reduced NO and PGE2 production, although an overexpression of IL-1β, IL-6 and IL-10 was observed. Finally, all nanoparticles proved to be biocompatible in a subcutaneous injection model in rats. These findings suggest that these loaded nanoparticles could be suitable candidates for the treatment of inflammatory processes associated with osteoarthritis due to their demonstrated in vitro activity as reg-ulators of inflammatory mediator production.

Pontes-Quero, G. M., Benito-Garzón, L., Pérez Cano, J., Aguilar, M. R. & Vázquez-Lasa, B. Modulation of Inflammatory Mediators by Polymeric Nanoparticles Loaded with Anti-Inflammatory Drugs. Pharmaceutics 13, 290 (2021). Cite

Vitamin B9 derivatives as carriers of bioactive cations for musculoskeletal regeneration applications: Synthesis, characterization and biological evaluation

The development of new drugs for musculoskeletal regeneration purposes has attracted much attention in the last decades. In this work, we present three novel vitamin B9 (folic acid)-derivatives bearing divalent cations (ZnFO, MgFO and MnFO), providing their synthesis mechanism and physicochemical characterization. In addition, a strong emphasis has been placed on evaluating their biological properties (along with our previously reported SrFO) using human mesenchymal stem cells (hMSC). In all the cases, pure folate derivatives (MFOs) with a bidentate coordination mode between the metal and the folate anion, and a 1:1 stoichiometry, were obtained in high yields. A non-cytotoxic dose of all the MFOs (50 μg/mL) was demonstrated to modulate by their own the mRNA profiles towards osteogenic-like or fibrocartilaginous-like phenotypes in basal conditions. Moreover, ZnFO increased the alkaline phosphatase activity in basal conditions, while both ZnFO and MnFO increased the matrix mineralization degree in osteoinductive conditions. Thus, we have demonstrated the bioactivity of these novel compounds and the suitability to further studied them in vivo for musculoskeletal regeneration applications.

Antibacterial Bio-Based Polymers for Cranio-Maxillofacial Regeneration Applications

Cranio-maxillofacial structure is a region of particular interest in the field of regenerative medicine due to both its anatomical complexity and the numerous abnormalities affecting this area. However, this anatomical complexity is what makes possible the coexistence of different microbial ecosystems in the oral cavity and the maxillofacial region, contributing to the increased risk of bacterial infections. In this regard, different materials have been used for their application in this field. These materials can be obtained from natural and renewable feedstocks, or by synthetic routes with desired mechanical properties, biocompatibility and antimicrobial activity. Hence, in this review, we have focused on bio-based polymers which, by their own nature, by chemical modifications of their structure, or by their combination with other elements, provide a useful antibacterial activity as well as the suitable conditions for cranio-maxillofacial tissue regeneration. This approach has not been reviewed previously, and we have specifically arranged the content of this article according to the resulting material and its corresponding application; we review guided bone regeneration membranes, bone cements and devices and scaffolds for both soft and hard maxillofacial tissue regeneration, including hybrid scaffolds, dental implants, hydrogels and composites.

Martín-del-Campo, M., Fernández-Villa, D., Cabrera-Rueda, G. & Rojo, L. Antibacterial Bio-Based Polymers for Cranio-Maxillofacial Regeneration Applications. Applied Sciences 10, 8371 (2020). Cite

Amphiphilic polymeric nanoparticles encapsulating curcumin: Antioxidant, anti-inflammatory and biocompatibility studies

Oxidative stress and inflammation are two related processes common to many diseases. Curcumin is a natural compound with both antioxidant and anti-inflammatory properties, among others, that is recently being used as a natural occurring product alternative to traditional drugs. However, it has a hydrophobic nature that compromises its solubility in physiological fluids and its circulation time and also presents cytotoxicity problems in its free form, limiting the range of concentrations to be used. In order to overcome these drawbacks and taking advantage of the benefits of nanotechnology, the aim of this work is the development of curcumin loaded polymeric nanoparticles that can provide a controlled release of the drug and enlarge their application in the treatment of inflammatory and oxidative stress related diseases. Specifically, the vehicle is a bioactive terpolymer based on a α-tocopheryl methacrylate, 1-vinyl-2-pyrrolidone and N-vinylcaprolactam. Nanoparticles were obtained by nanoprecipitation and characterized in terms of size, morphology, stability, encapsulation efficiency and drug release. In vitro cellular assays were performed in human articular chondrocyte and RAW 264.7 cultures to assess cytotoxicity, cellular uptake, antioxidant and anti-inflammatory properties. The radical scavenging activity of the systems was confirmed by the DPPH test and the quantification of cellular reactive oxygen species. The anti-inflammatory potential of these systems was demonstrated by the reduction of different pro-inflammatory factors such as IL-8, MCP and MIP in chondrocytes; and nitric oxide, IL-6, TNF-α and MCP-1, among others, in RAW 264.7. Finally, the in vivo biocompatibility was confirmed in a rat model by subcutaneously injecting the nanoparticle dispersions. The reduction of curcumin toxicity and the antioxidant, anti-inflammatory and biocompatibility properties open the door to deeper in vitro and in vivo research on these curcumin loaded polymeric nanoparticles to treat inflammation and oxidative stress based diseases.

Pontes-Quero, G. M., Benito-Garzón, L., Pérez Cano, J., Aguilar, M. R. & Vázquez-Lasa, B. Amphiphilic polymeric nanoparticles encapsulating curcumin: Antioxidant, anti-inflammatory and biocompatibility studies. Materials Science and Engineering: C 121, 111793 (2021). Cite

Evaluation of glycerylphytate crosslinked semi-and interpenetrated polymer membranes of hyaluronic acid and chitosan for tissue engineering

In the present study, semi-and interpenetrated polymer network (IPN) systems based on hyaluronic acid (HA) and chitosan using ionic crosslinking of chitosan with a bioactive crosslinker, glycerylphytate (G1Phy), and UV irradiation of methacrylate were developed, characterized and evaluated as potential supports for tissue engineering. Semi-and IPN systems showed significant differences between them regarding composition, morphology, and mechanical properties after physicochemical characterization. Dual crosslinking process of IPN systems enhanced HA retention and mechanical properties, providing also flatter and denser surfaces in comparison to semi-IPN membranes. The biological performance was evaluated on primary human mesenchymal stem cells (hMSCs) and the systems revealed no cytotoxic effect. The excellent biocompatibility of the systems was demonstrated by large spreading areas of hMSCs on hydrogel membrane surfaces. Cell proliferation increased over time for all the systems, being significantly enhanced in the semi-IPN, which suggested that these polymeric membranes could be proposed as an effective promoter system of tissue repair. In this sense, the developed crosslinked biomimetic and biodegradable membranes can provide a stable and amenable environment for hMSCs support and growth with potential applications in the biomedical field.

Microfluidics generation of chitosan microgels containing glycerylphytate crosslinker for in situ human mesenchymal stem cells encapsulation

Human mesenchymal stem cells (hMSCs) are an attractive source for cell therapies because of their multiple beneficial properties, i.e. via immunomodulation and secretory factors. Microfluidics is particularly attractive for cell encapsulation since it provides a rapid and reproducible methodology for microgel generation of controlled size and simultaneous cell encapsulation. Here, we report the fabrication of hMSC-laden microcarriers based on in situ ionotropic gelation of water-soluble chitosan in a microfluidic device using a combination of an antioxidant glycerylphytate (G1Phy) compound and tripolyphosphate (TPP) as ionic crosslinkers (G1Phy:TPP-microgels). These microgels showed homogeneous size distributions providing an average diameter of 104 ± 12 μm, somewhat lower than that of control (127 ± 16 μm, TPP-microgels). The presence of G1Phy in microgels maintained cell viability over time and upregulated paracrine factor secretion under adverse conditions compared to control TPP-microgels. Encapsulated hMSCs in G1Phy:TPP-microgels were delivered to the subcutaneous space of immunocompromised mice via injection, and the delivery process was as simple as the injection of unencapsulated cells. Immediately post-injection, equivalent signal intensities were observed between luciferase-expressing microgel-encapsulated and unencapsulated hMSCs, demonstrating no adverse effects of the microcarrier on initial cell survival. Cell persistence, inferred by bioluminescence signal, decreased exponentially over time showing relatively higher half-life values for G1Phy:TPP-microgels compared to TPP-microgels and unencapsulated cells. In overall, results position the microfluidics generated G1Phy:TPP-microgels as a promising microcarrier for supporting hMSC survival and reparative activities.

Chitosan-stabilized silver nanoclusters with luminescent, photothermal and antibacterial properties

The aim of this paper is to achieve in situ photochemical synthesis of silver nanoclusters (AgNCs) stabilized by the multiple-amine groups of chitosan (Ch@AgNCs) with luminescent and photothermal properties. Ch@AgNCs were obtained by applying a fast and simple methodology previously described by our group. Direct functionalization of AgNCs with chitosan template provided new nanohybrids directly in water solution, both in the presence or absence of oxygen. The formation of hybrid AgNCs could be monitored by the rapid increase of the absorption and emission maximum band with light irradiation time. New Ch@AgNCs not only present photoluminescent properties but also photothermal properties when irradiated with near infrared light (NIR), transducing efficiently NIR into heat and increasing the temperature of the medium up to 23 °C. The chitosan polymeric shell associated to AgNCs works as a protective support stabilizing the metal cores, facilitating the storage of nanohybrids and preserving luminescent, photothermal and bactericide properties.

Nakal-Chidiac, A. et al. Chitosan-stabilized silver nanoclusters with luminescent, photothermal and antibacterial properties. Carbohydrate Polymers 250, 116973 (2020). Cite

Polymeric Nanoparticles that Combine Dexamethasone and Naproxen for the Synergistic Inhibition of Il12b Transcription in Macrophages

Recent studies have demonstrated in vivo synergistic immunosuppressive and anti‐inflammatory capacity of dexamethasone (Dx) and naproxen (NAP) in collagen‐induced arthritis (CIA) rats. However, the molecular basis of this synergistic effect is barely understood. The low solubility of these drugs and their adverse effects hamper their efficacy on the treatment of inflammatory processes making nanoparticulated systems promising candidates to overcome these drawbacks. The aim of this work is the preparation of polymeric nanoparticles (NPs) that combine NAP and Dx in different concentrations, and the evaluation of the expression of key genes related to autoimmune diseases like CIA. To do so, self‐assembled polymeric NPs that incorporate covalently‐linked NAP and physically entrapped Dx are designed to have hydrodynamic properties that, according to bibliography, may improve retention and colocalization of both drugs at inflammation sites. The rapid uptake of NPs by macrophages is demonstrated using coumarine‐6‐loaded NPs. Dx is efficiently encapsulated and in vitro biological studies demonstrate that the Dx‐loaded NAP‐bearing NPs are noncytotoxic and reduce lipopolysaccharide‐induced NO released levels at any of the tested concentrations. Moreover, at the molecular level, a significant synergistic reduction of Il12b transcript gene expression when combining Dx and NAP is demonstrated.

Espinosa‐Cano, E., Aguilar, M. R., Portilla, Y., Barber, D. F. & Román, J. S. Polymeric Nanoparticles that Combine Dexamethasone and Naproxen for the Synergistic Inhibition of Il12b Transcription in Macrophages. Macromolecular Bioscience 20, 2000002 (2020). Cite
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