Prevascularized spongy-like hydrogels maintain their angiogenic potential after prolonged hypothermic storage.

The chronic shortage of organs and tissues for transplantation represents a dramatic burden on healthcare systems worldwide. Tissue engineering offers a potential solution to address these shortages, but several challenges remain, with prevascularization being a critical factor for in vivo survival and integration of tissue engineering products. Concurrently, a different challenge hindering the clinical implementation of such products, regards their efficient preservation from the fabrication site to the bedside. Hypothermia has emerged as a potential solution for this issue due to its milder effects on biologic systems in comparison with other cold preservation methodologies. Its impact on prevascularization, however, has not been well studied. In this work, 3D prevascularized constructs were fabricated using adipose-derived stromal vascular fraction cells and preserved at 4 °C using Hypothermosol or basal culture media (α-MEM). Hypothermosol efficiently preserved the structural and cellular integrity of prevascular networks as compared to constructs before preservation. In contrast, the use of α-MEM led to a clear reduction in prevascular structures, with concurrent induction of high levels of apoptosis and autophagy at the cellular level. In vivo evaluation using a chorioallantoic membrane model demonstrated that, in opposition to α-MEM, Hypothermosol preservation retained the angiogenic potential of constructs before preservation by recruiting a similar number of blood vessels from the host and presenting similar integration with host tissue. These results emphasize the need of studying the impact of preservation techniques on key properties of tissue engineering constructs such as prevascularization, in order to validate and streamline their clinical application.

Oral exosome-like nanovesicles from Phellinus linteus suppress metastatic hepatocellular carcinoma by reactive oxygen species generation and microbiota rebalancing.

The biomedical application of nanotechnology in cancer treatment has demonstrated significant potential for improving treatment efficiencies and ameliorating adverse effects. However, the medical translation of nanotechnology-based nanomedicines faces challenges including hazardous environmental effects, difficulties in large-scale production, and possible excessive costs. In the present study, we extracted and purified natural exosome-like nanoparticles (ELNs) from Phellinus linteus. These nanoparticles (denoted as P-ELNs) had an average particle size of 154.1 nm, displayed a negative zeta potential of -31.3 mV, and maintained stability in the gastrointestinal tract. Furthermore, P-ELNs were found to contain a diverse array of functional components, including lipids and pharmacologically active small-molecule constituents. In vitro investigations suggested that they exhibited high internalization efficiency in liver tumor cells (Hepa 1-6) and exerted significant anti-proliferative, anti-migratory, and anti-invasive effects against Hepa 1-6 cells. Strikingly, the therapeutic outcomes of oral P-ELNs were confirmed in an animal model of metastatic hepatocellular carcinoma by amplifying reactive oxygen species (ROS) and rebalancing the gut microbiome. These findings demonstrate the potential of P-ELNs as a promising oral therapeutic platform for liver cancer treatment.

In vivo assessment of marine vs bovine origin collagen-based composite scaffolds promoting bone regeneration in a New Zealand rabbit model.

The ability of human tissues to self-repair is limited, which motivates the scientific community to explore new and better therapeutic approaches to tissue regeneration. The present manuscript provides a comparative study between a marine-based composite biomaterial, and another composed of well-established counterparts for bone tissue regeneration. Blue shark skin collagen was combined with bioapatite obtained from blue shark's teeth (mColl:BAp), while bovine collagen was combined with synthetic hydroxyapatite (bColl:Ap) to produce 3D composite scaffolds by freeze-drying. Collagens showed similar profiles, while apatite particles differed in their composition, being the marine bioapatite a fluoride-enriched ceramic. The marine-sourced biomaterials presented higher porosities, improved mechanical properties, and slower degradation rates when compared to synthetic apatite-reinforced bovine collagen. The in vivo performance regarding bone tissue regeneration was evaluated in defects created in femoral condyles in New Zealand rabbits twelve weeks post-surgery. Micro-CT results showed that mColl:BAp implanted condyles had a slower degradation and an higher tissue formation (17.9 ± 6.9 %) when compared with bColl:Ap implanted ones (12.9 ± 7.6 %). The histomorphometry analysis provided supporting evidence, confirming the observed trend by quantifying 13.1 ± 7.9 % of new tissue formation for mColl:BAp composites and 10.4 ± 3.2 % for bColl:Ap composites, suggesting the potential use of marine biomaterials for bone regeneration.

Humanistic Health Management and Cancer: Associations of Psychology, Nutrition, and Exercise with Cancer Progression and Pathogenesis.

The incidence rate of cancer is increasing year by year due to the aging of the population, unhealthy living, and eating habits. At present, surgery and medication are still the main treatments for cancer, without paying attention to the impact of individual differences in health management on cancer. However, increasing evidence suggests that individual psychological status, dietary habits, and exercise frequency are closely related to the risk and prognosis of cancer. The reminder to humanity is that the medical concept of the unified treatment plan is insufficient in cancer treatment, and a personalized treatment plan may become a breakthrough point. On this basis, the concept of "Humanistic Health Management" (HHM) is proposed. This concept is a healthcare plan that focuses on self-health management, providing an accurate and comprehensive evaluation of individual lifestyle habits, psychology, and health status, and developing personalized and targeted comprehensive cancer prevention and treatment plans. This review will provide a detailed explanation of the relationship between psychological status, dietary, and exercise habits, and the regulatory mechanisms of cancer. Intended to emphasize the importance of HHM concept in cancer prevention and better prognostic efficacy, providing new ideas for the new generation of cancer treatment.

Magnetic natural lipid nanoparticles for oral treatment of colorectal cancer through potentiated antitumor immunity and microbiota metabolite regulation.

The therapeutic efficacy of oral nanotherapeutics against colorectal cancer (CRC) is restricted by inadequate drug accumulation, immunosuppressive microenvironment, and intestinal microbiota imbalance. To overcome these challenges, we elaborately constructed 6-gingerol (Gin)-loaded magnetic mesoporous silicon nanoparticles and functionalized their surface with mulberry leaf-extracted lipids (MLLs) and Pluronic F127 (P127). In vitro experiments revealed that P127 functionalization and alternating magnetic fields (AMFs) promoted internalization of the obtained P127-MLL@Gins by colorectal tumor cells and induced their apoptosis/ferroptosis through Gin/ferrous ion-induced oxidative stress and magneto-thermal effect. After oral administration, P127-MLL@Gins safely passed to the colorectal lumen, infiltrated the mucus barrier, and penetrated into the deep tumors under the influence of AMFs. Subsequently, the P127-MLL@Gin (+ AMF) treatment activated antitumor immunity and suppressed tumor growth. We also found that this therapeutic modality significantly increased the abundance of beneficial bacteria (e.g., Bacillus and unclassified-c-Bacilli), reduced the proportions of harmful bacteria (e.g., Bacteroides and Alloprevotella), and increased lipid oxidation metabolites. Strikingly, checkpoint blockers synergistically improved the therapeutic outcomes of P127-MLL@Gins (+ AMF) against orthotopic and distant colorectal tumors and significantly prolonged mouse life spans. Overall, this oral therapeutic platform is a promising modality for synergistic treatment of CRC.

Chitosan/Virgin Coconut Oil-Based Emulsions Doped with Photosensitive Curcumin Loaded Capsules: A Functional Carrier to Topical Treatment.

In recent years, there has been a growing interest in developing smart drug delivery systems based on natural resources combined with stimulus-sensitive elements. This trend aims to formulate innovative and sustainable delivery platforms tailored for topical applications. This work proposed the use of layer-by-layer (LbL) methodology to fabricate biocompatible photo-responsive multilayer systems. These systems are composed of a polyoxometalate inorganic salt (POM) ([NaP5W30O110]14-) and a natural origin polymer, chitosan (CHT). Curcumin (CUR), a natural bioactive compound, was incorporated to enhance the functionality of these systems during the formation of hollow capsules. The capsules produced, with sizes between 2-5µm (SEM), were further dispersed into CHT/VCO (virgin coconut oil) emulsion solutions that were casted into molds and dried at 37 °C for 48 h. The system presented a higher water uptake in PBS than in acidic conditions, still significantly lower than that earlier reported to other CHT/VCO-based systems. The drug release profile is not significantly influenced by the medium pH reaching a maximum of 37% ± 1% after 48 h. The antioxidant performance of the designed structures was further studied, suggesting a synergistic beneficial effect resulting from CUR, POM, and VCO individual bioactivities. The increased amount of those excipients released to the media over time promoted an increase in the antioxidant activity of the system, reaching a maximum of 38.1% ± 0.1% after 48 h. This work represents a promising step towards developing advanced, sustainable drug delivery systems for topical applications.

The Characterization and Cytotoxic Evaluation of Chondrosia reniformis Collagen Isolated from Different Body Parts (Ectosome and Choanosome) Envisaging the Development of Biomaterials.

Chondrosia reniformis is a collagen-rich marine sponge that is considered a sustainable and viable option for producing an alternative to mammalian-origin collagens. However, there is a lack of knowledge regarding the properties of collagen isolated from different sponge parts, namely the outer region, or cortex, (ectosome) and the inner region (choanosome), and how it affects the development of biomaterials. In this study, a brief histological analysis focusing on C. reniformis collagen spatial distribution and a comprehensive comparative analysis between collagen isolated from ectosome and choanosome are presented. The isolated collagen characterization was based on isolation yield, Fourier-transformed infrared spectroscopy (FTIR), circular dichroism (CD), SDS-PAGE, dot blot, and amino acid composition, as well as their cytocompatibility envisaging the development of future biomedical applications. An isolation yield of approximately 20% was similar for both sponge parts, as well as the FTIR, CD, and SDS-PAGE profiles, which demonstrated that both isolated collagens presented a high purity degree and preserved their triple helix and fibrillar conformation. Ectosome collagen had a higher OHpro content and possessed collagen type I and IV, while the choanosome was predominately constituted by collagen type IV. In vitro cytotoxicity assays using the L929 fibroblast cell line displayed a significant cytotoxic effect of choanosome collagen at 2 mg/mL, while ectosome collagen enhanced cell metabolism and proliferation, thus indicating the latter as being more suitable for the development of biomaterials. This research represents a unique comparative study of C. reniformis body parts, serving as a support for further establishing this marine sponge as a promising alternative collagen source for the future development of biomedical applications.

Generation of 3D melanoma models using an assembloid-based approach.

While 3D tumor models have greatly evolved over the past years, there is still a strong requirement for more biosimilar models which are capable of recapitulating cellular crosstalk within the tumor microenvironment while equally displaying representative levels of tumor aggressiveness and invasion. Herein, we disclose an assembloid melanoma model based on the fusion of individual stromal multicellular spheroids (MCSs). In contrast to more traditional tumor models, we show that it is possible to develop self-organizing, heterotypic melanoma models where tumor cells present stem-cell like features like up-regulated pluripotency master regulators SOX2, POU5F1 and NANOG. Additionally, these assembloids display high levels of invasiveness while embedded in 3D matrices as evidenced by stromal cell promotion of melanoma cell invasion via metalloproteinase production. Furthermore, sensitivity to anticancer drug doxorubicin was demonstrated for the melanoma assembloid model. These findings suggest that melanoma assembloids may play a significant role in the field of 3D cancer models as they more closely mimic the tumor microenvironment when compared to more traditional MCSs, opening the doors to a better understanding of the role of tumor microenvironment in supporting tumor progression. STATEMENT OF SIGNIFICANCE: The development of complex 3D tumor models that better recapitulate the tumor microenvironment is crucial for both an improved comprehension of intercellular crosstalk and for more efficient drug screening. We have herein developed a self-organizing heterotypic assembloid-based melanoma model capable of closely mimicking the tumor microenvironment. Key features recapitulated were the preservation of cancer cell stemness, sensitivity to anti-cancer agents and tumor cell invasion promoted by stromal cells. The approach of pre-establishing distinct stromal domains for subsequent combination into more complex tumor constructs provides a route for developing superior tumor models with a higher degree of similarity to native cancer tissues.

Co-axial hydrogel spinning for facile biofabrication of prostate cancer-like 3D models.

Glandular cancers are amongst the most prevalent types of cancer, which can develop in many different organs, presenting challenges in their detection as well as high treatment variability and failure rates. For that purpose, anticancer drugs are commonly tested in cancer cell lines grown in 2D tissue culture on plastic dishesin vitro, or in animal modelsin vivo. However, 2D culture models diverge significantly from the 3D characteristics of living tissues and animal models require extensive animal use and time. Glandular cancers, such as prostate cancer-the second leading cause of male cancer death-typically exist in co-centrical architectures where a cell layer surrounds an acellular lumen. Herein, this spatial cellular position and 3D architecture, containing dual compartments with different hydrogel materials, is engineered using a simple co-axial nozzle setup, in a single step utilizing prostate as a model of glandular cancer. The resulting hydrogel soft structures support viable prostate cancer cells of different cell lines and enable over-time maturation into cancer-mimicking aggregates surrounding the acellular core. The biofabricated cancer mimicking structures are then used as a model to predict the inhibitory efficacy of the poly ADP ribose polymerase inhibitor, Talazoparib, and the antiandrogen drug, Enzalutamide, in the growth of the cancer cell layer. Our results show that the obtained hydrogel constructs can be adapted to quickly obtain 3D cancer models which combine 3D physiological architectures with high-throughput screening to detect and optimize anti-cancer drugs in prostate and potentially other glandular cancer types.

Bioadhesive Hyaluronic Acid-Based Hydrogels for Spinal Cord Injury.

Spinal cord injuries (SCI) have devastating physical, psychological, and psychosocial consequences for patients. One challenge of nerve tissue repair is the lack of a natural extracellular matrix (ECM) that guides the regenerating axons. Hyaluronic acid (HA) is a major ECM component and plays a fundamental role in facilitating lesion healing. Herein, we developed HA-based adhesive hydrogels by modification of HA with dopamine, a mussel-inspired compound with excellent adhesive properties in an aqueous environment. The hydrogels were loaded with the anti-inflammatory drug ibuprofen and the response of neuronal cells (SH-SY5Y) was evaluated in terms of viability, morphology, and adhesion. The obtained results suggested that the developed materials can bridge lesion gaps, guide axonal growth, and simultaneously act as a vehicle for the delivery of bioactive compounds.

Extracellular matrix-derived materials for tissue engineering and regenerative medicine: A journey from isolation to characterization and application.

Biomaterial choice is an essential step during the development tissue engineering and regenerative medicine (TERM) applications. The selected biomaterial must present properties allowing the physiological-like recapitulation of several processes that lead to the reestablishment of homeostatic tissue or organ function. Biomaterials derived from the extracellular matrix (ECM) present many such properties and their use in the field has been steadily increasing. Considering this growing importance, it becomes imperative to provide a comprehensive overview of ECM biomaterials, encompassing their sourcing, processing, and integration into TERM applications. This review compiles the main strategies used to isolate and process ECM-derived biomaterials as well as different techniques used for its characterization, namely biochemical and chemical, physical, morphological, and biological. Lastly, some of their applications in the TERM field are explored and discussed.

Tissue adhesives based on chitosan for skin wound healing: Where do we stand in this era? A review.

Chitosan has been commonly used as an adhesive dressing material due to its excellent biocompatibility, degradability, and renewability. Tissue adhesives are outstanding among wound dressings because they can close the wound, absorb excess tissue exudate from the wound site, provide a moist environment, and act as a carrier for loading various bioactive molecules. They have been widely used in both preclinical and clinical treatment of skin wounds. This review summarizes recent research progresses in the application of chitosan and its derivatives for tissue adhesives. We also introduce their biomedical effects on wound adhesion, contamination isolation, antibacterial, immune regulation, and wound healing, and the strategies to achieve these functions when used as wound dressings. Finally, challenges and future perspectives of chitosan-based tissue adhesives are discussed for wound healing.

Mulberry Leaf Lipid Nanoparticles: a Naturally Targeted CRISPR/Cas9 Oral Delivery Platform for Alleviation of Colon Diseases.

Oral treatment of colon diseases with the CRISPR/Cas9 system has been hampered by the lack of a safe and efficient delivery platform. Overexpressed CD98 plays a crucial role in the progression of ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC). In this study, lipid nanoparticles (LNPs) derived from mulberry leaves are functionalized with Pluronic copolymers and optimized to deliver the CRISPR/Cas gene editing machinery for CD98 knockdown. The obtained LNPs possessed a hydrodynamic diameter of 267.2 nm, a narrow size distribution, and a negative surface charge (-25.6 mV). Incorporating Pluronic F127 into LNPs improved their stability in the gastrointestinal tract and facilitated their penetration through the colonic mucus barrier. The galactose end groups promoted endocytosis of the LNPs by macrophages via asialoglycoprotein receptor-mediated endocytosis, with a transfection efficiency of 2.2-fold higher than Lipofectamine 6000. The LNPs significantly decreased CD98 expression, down-regulated pro-inflammatory cytokines (TNF-α and IL-6), up-regulated anti-inflammatory factors (IL-10), and polarized macrophages to M2 phenotype. Oral administration of LNPs mitigated UC and CAC by alleviating inflammation, restoring the colonic barrier, and modulating intestinal microbiota. As the first oral CRISPR/Cas9 delivery LNP, this system offers a precise and efficient platform for the oral treatment of colon diseases.

Natural lipid nanoparticles extracted from Morus nigra L. leaves for targeted treatment of hepatocellular carcinoma via the oral route.

The clinical application of conventional medications for hepatocellular carcinoma treatment has been severely restricted by their adverse effects and unsatisfactory therapeutic effectiveness. Inspired by the concept of 'medicine food homology', we extracted and purified natural exosome-like lipid nanoparticles (LNPs) from black mulberry (Morus nigra L.) leaves. The obtained MLNPs possessed a desirable hydrodynamic particle size (162.1 nm), a uniform size distribution (polydispersity index = 0.025), and a negative surface charge (-26.6 mv). These natural LNPs were rich in glycolipids, functional proteins, and active small molecules (e.g., rutin and quercetin 3-O-glucoside). In vitro experiments revealed that MLNPs were preferentially internalized by liver tumor cell lines via galactose receptor-mediated endocytosis, increased intracellular oxidative stress, and triggered mitochondrial damage, resulting in suppressing the viability, migration, and invasion of these cells. Importantly, in vivo investigations suggested that oral MLNPs entered into the circulatory system mainly through the jejunum and colon, and they exhibited negligible adverse effects and superior anti-liver tumor outcomes through direct tumor killing and intestinal microbiota modulation. These findings collectively demonstrate the potential of MLNPs as a natural, safe, and robust nanomedicine for oral treatment of hepatocellular carcinoma.

Modelling the complex nature of the tumor microenvironment: 3D tumor spheroids as an evolving tool.

Cancer remains a serious burden in society and while the pace in the development of novel and more effective therapeutics is increasing, testing platforms that faithfully mimic the tumor microenvironment are lacking. With a clear shift from animal models to more complex in vitro 3D systems, spheroids emerge as strong options in this regard. Years of development have allowed spheroid-based models to better reproduce the biomechanical cues that are observed in the tumor-associated extracellular matrix (ECM) and cellular interactions that occur in both a cell-cell and cell-ECM manner. Here, we summarize some of the key cellular interactions that drive tumor development, progression and invasion, and how successfully are these interactions recapitulated in 3D spheroid models currently in use in the field. We finish by speculating on future advancements in the field and on how these can shape the relevance of spherical 3D models for tumor modelling.

Evaluation of novel dendrimer-gold complex nanoparticles for theranostic application in oncology.

Aim: Despite some successful examples of therapeutic nanoparticles reaching clinical stages, there is still a significant need for novel formulations in order to improve the selectivity and efficacy of cancer treatment. Methods: The authors developed two novel dendrimer-gold (Au) complex-based nanoparticles using two different synthesis routes: complexation method (formulation A) and precipitation method (formulation B). Using a biomimetic cancer-on-a-chip model, the authors evaluated the possible cytotoxicity and internalization by colorectal cancer cells of dendrimer-Au complex-based nanoparticles. Results: The results showed promising capabilities of these nanoparticles for selectively targeting cancer cells and delivering drugs, particularly for the formulation A nanoparticles. Conclusion: This work highlights the potential of dendrimer-Au complex-based nanoparticles as a new strategy to improve the targeting of anticancer drugs.

An Oral Nanomedicine Elicits In Situ Vaccination Effect against Colorectal Cancer.

Oral administration is the most preferred approach for treating colon diseases, and in situ vaccination has emerged as a promising cancer therapeutic strategy. However, the lack of effective drug delivery platforms hampered the application of in situ vaccination strategy in oral treatment of colorectal cancer (CRC). Here, we construct an oral core-shell nanomedicine by preparing a silk fibroin-based dual sonosensitizer (chlorin e6, Ce6)- and immunoadjuvant (imiquimod, R837)-loaded nanoparticle as the core, with its surface coated with plant-extracted lipids and pluronic F127 (p127). The resultant nanomedicines (Ce6/R837@Lp127NPs) maintain stability during their passage through the gastrointestinal tract and exert improved locomotor activities under ultrasound irradiation, achieving efficient colonic mucus infiltration and specific tumor penetration. Thereafter, Ce6/R837@Lp127NPs induce immunogenic death of colorectal tumor cells by sonodynamic treatment, and the generated neoantigens in the presence of R837 serve as a potent in situ vaccine. By integrating with immune checkpoint blockades, the combined treatment modality inhibits orthotopic tumors, eradicates distant tumors, and modulates intestinal microbiota. As the first oral in situ vaccination, this work spotlights a robust oral nanoplatform for producing a personalized vaccine against CRC.

COX-2 inhibitor delivery system aiming intestinal inflammatory disorders.

Selective COX-2 inhibitors such as etoricoxib (ETX) are potentially indicated for the treatment of intestinal inflammatory disorders. However, their systemic administration provokes some off-site secondary effects, decreasing the desirable local effectiveness. To circumvent such limitations, herein an ETX delivery system based on electrospun fibrous meshes (eFMs) was proposed. ETX at different concentrations (1, 2, and 3 mg mL-1) was loaded into eFMs, which not affect the morphology and the mechanical properties of this drug delivery system (DDS). The ETX showed a burst release within the first 12 h, followed by a faster release until 36 h, gradually decreasing over time. Importantly, the ETX studied concentrations were not toxic to human colonic cells (i.e. epithelial and fibroblast). Moreover, the DDS loading the highest concentration of ETX, when tested with stimulated human macrophages, promoted a reduction of PGE2, IL-8 and TNF-α secretion. Therefore, the proposed DDS may constitute a safe and efficient treatment of colorectal diseases promoted by inflammatory disorders associated with COX-2.

Facilely printed silk fibroin hydrogel microparticles as injectable long-lasting fillers.

There is a high demand from aging people for facial fillers with desirable biocompatibility and lasting filling effects to overcome facial depression. Novel injectable regenerated silk fibroin (RSF) microparticles were facilely printed from a glycidyl methacrylate-modified silk fibroin hydrogel to address this issue. The ß-sheet content and mechanical properties of the RSF hydrogel can be simply modulated by the number of freeze-thawing cycles, and the swelling rate of the RSF hydrogel in saline was negligible. The printed RSF microparticles were uniform, and their diameter was about 300-500 µm, which could be adjusted by the pore sizes of the printed screens. After the injection with a 26-gauge needle, the size distribution of RSF microparticles had no noticeable variation, suggesting that the microparticles could bear the shear strain without breaking during the injection. The in vitro experiments demonstrated that RSF not only had desirable biocompatibility but also facilitated fibroblast migration. The subcutaneous injection experiments demonstrated that the RSF microparticles formed a lasting spot in the injected site. The tissue sections revealed that the RSF microparticles were still distinct on week 8, and blood vessels formed around the microparticles. These promising data demonstrate that the printed RSF microparticles have great potential for facial rejuvenation.

3D bioactive ionic liquid-based architectures: An anti-inflammatory approach for early-stage osteoarthritis.

3D bioprinting enables the fabrication of biomimetic cell-laden constructs for cartilage regeneration, offering exclusive strategies for precise pharmacological screenings in osteoarthritis (OA). Synovial inflammation plays a crucial role in OA's early stage and progression, characterized by the increased of the synovial pro-inflammatory mediators and cytokines and chondrocyte apoptosis. Therefore, there is an urgent need to develop solutions for effectively managing the primary events associated with OA. To address these issues, a phenolic-based biocompatible ionic liquid approach, combining alginate (ALG), acemannan (ACE), and cholinium caffeate (Ch[Caffeate]), was used to produce easily printable bioinks. Through the use of this strategy 3D constructs with good printing resolution and high structural integrity were obtained. The encapsulation of chondrocytes like ATDC5 cells provided structures with good cell distribution, viability, and growth, for up to 14 days. The co-culture of the constructs with THP-1 macrophages proved their ability to block pro-inflammatory cytokines (TNF-α and IL-6) and mediators (GM-CSF), released by the cultured cells. Moreover, incorporating the biocompatible ionic liquid into the system significantly improved its bioactive performance without compromising its physicochemical features. These findings demonstrate that ALG/ACE/Ch[Caffeate] bioinks have great potential for bioengineering cartilage tissue analogs. Besides, the developed ALG/ACE/Ch[Caffeate] bioinks protected encapsulated chondrocyte-like cells from the effect of the inflammation, assessed by a co-culture system with THP-1 macrophages. These results support the increasing use of Bio-ILs in the biomedical field, particularly for developing 3D bioprinting-based constructs to manage inflammatory-based changes in OA. STATEMENT OF SIGNIFICANCE: Combining natural resources with active biocompatible ionic liquids (Bio-IL) for 3D printing is herein presented as an approach for the development of tools to manage inflammatory osteoarthritis (OA). We propose combining alginate (ALG), acemannan (ACE), and cholinium caffeate (Ch[Caffeate]), a phenolic-based Bio-IL with anti-inflammatory and antioxidant features, to produce bioinks that allow to obtain 3D constructs with good printing resolution, structural integrity, and that provide encapsulated chondrocyte-like cells good viability. The establishment of a co-culture system using the printed constructs and THP-1-activated macrophages allowed us to study the encapsulated chondrocyte-like cells behaviour within an inflammatory scenario, a typical event in early-stage OA. The obtained outcomes support the beneficial use of Bio-ILs in the biomedical field, particularly for the development of 3D bioprinting-based models that allow the monitoring of inflammatory-based events in OA.