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Given the importance of the extracellular medium during tissue formation, it was wise to develop an artificial structure that mimics the extracellular matrix while having improved physico-chemical properties. That is why the choice was focused on gelatin methacryloyl (GelMA), an inexpensive biocompatible hydrogel. Physicochemical and mechanical properties were improved by the incorporation of nanoparticles developed from two innovative fabrication processes: High shear fluid and low frequencies/high frequencies ultrasounds. Both rapeseed nanoliposomes and nanodroplets were successfully incorporated in the GelMA networks during the photo polymerization process. The impact on polymer microstructure was investigated by Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and enzymatic degradation investigations. Mechanical stability and viscoelastic tests were conducted to demonstrate the beneficial effect of the functionalization on GelMA hydrogels. Adding nanoparticles to GelMA improved the surface properties (porosity), tuned swelling, and degradability properties. In addition, we observed that nanoemulsion didn’t change significantly the mechanical properties to shear and compression solicitations, whereas nanoliposome addition decreased Young’s modulus under compression solicitations. Thus, these ways of functionalization allow controlling the design of the material by choosing the type of nanoparticle (nanoliposome or nanoemulsion) in function of the application.

Hydrogels with protein–polysaccharide combinations are widely used in the field of tissue engineering, as they can mimic the in vivo environments of native tissues, specifically the extracellular matrix (ECM). However, achieving stability and mechanical properties comparable to those of tissues by employing natural polymers remains a challenge due to their weak structural characteristics. In this work, we optimized the fabrication strategy of a hydrogel composite, comprising gelatin and sodium alginate (Gel-SA), by varying reaction parameters. Magnetite (Fe3O4) nanoparticles were incorporated to enhance the mechanical stability and structural integrity of the scaffold. The changes in hydrogel stiffness and viscoelastic properties due to variations in polymer mixing ratio, crosslinking time, and heating cycle, both before and after nanoparticle incorporation, were compared. FTIR spectra of crosslinked hydrogels confirmed physical interactions of Gel-SA, metal coordination bonds of alginate with Ca2+, and magnetite nanoparticles. Tensile and rheology tests confirmed that even at low magnetite concentration, the Gel-SA-Fe3O4 hydrogel exhibits mechanical properties comparable to soft tissues. This work has demonstrated enhanced resilience of magnetite-incorporated Gel-SA hydrogels during the heating cycle, compared to Gel-SA gel, as thermal stability is a significant concern for hydrogels containing gelatin. The interactions of thermoreversible gelatin, anionic alginate, and nanoparticles result in dynamic hydrogels, facilitating their use as viscoelastic acellular matrices.

Chronic skin ulcers such as diabetic ulcers and venous leg ulcers are increasing and are a costly problem in healthcare. We have developed a novel artificial dermis, collagen/gelatin sponge (CGS), which is capable of sustained release of basic fibroblast growth factor (bFGF) for more than 10 days. The objective of this study was to investigate the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. Patients with chronic skin ulcers that had not healed in at least 4 weeks were treated with CGS impregnated with bFGF at 7 or 14 μg/cm 2 after debridement, and the wound bed improvement was assessed 14 days after application. Wound bed improvement was defined as a granulated and epithelialized area on day 14 with a proportion to the baseline wound area after debridement of 50% or higher. The wound area, the wound area on day 14, and the granulation area on day 14 were independently measured by blinded reviewers in a central review using digital images of wounds taken with a calibrator. Patients were followed up until 28 days after application to observe the adverse reactions related to the application of CGS. From May 2010 to June 2011, 17 patients were enrolled and, in 16 patients, the wound bed improved. Among the randomized patients in step 2, no significant difference was seen between the low-dose group and the high-dose group. No serious adverse reactions were observed. Adverse reactions with a clear causal relationship to the study treatment were mild and patients quickly recovered from them. This study is the first-in-man clinical trial of CGS and showed the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. This combination therapy could be a promising therapy for chronic skin ulcers.

Surgical resection of the tumor remains the preferred treatment for most solid tumors at an early stage, however, residual tumor cells after surgical resection poses a considerable obstacle in cancer treatment. Here, we developed a gel carrier using a cellulose-based gel-forming polymer (CT) combined with gelatin sponge (GS) to fill the resection cavity and delay postoperative residual tumor growth. The fabricated gel exhibited a porous nature along with gradual swelling and erosion over time. Curcumin (Cur) and apatinib (Apa) were loaded into CT gel (CT-CA), and a sustained release behavior was observed at pH 7.4 and 6.4 at 37 °C. The preclinical studies indicated that the mouse weight and tissue exhibited no apparent change after administration of the GS-CT compared with the control. The in vivo fluorescence images showed that GS-CT has the capability to regulate the release of Cur and Apa, facilitating the accumulation of these two agents at the surgical tumor site. Moreover, GS-CT loaded Cur and Apa (GS-CT-CA) delayed postoperative residual tumor growth in intraperitoneal and subcutaneous postoperative mouse models. These findings demonstrated that our gel carrier system significantly prevents postoperative residual tumor growth because of enhanced drug accumulation and sustained drug release at the tumor site.

Wound healing is an obvious clinical concern that can be hindered by inadequate angiogenesis, inflammation, and chronic hypoxia. While exosomes derived from adipose tissue-derived stem cells have shown promise in accelerating healing by carrying therapeutic growth factors and microRNAs, intracellular cargo delivery is compromised in hypoxic tissues due to activated hypoxia-induced endocytic recycling. To address this challenge, we have developed a strategy to coat oxygen nanobubbles with exosomes and incorporate them into a polyvinyl alcohol/gelatin hybrid hydrogel. This approach not only alleviates wound hypoxia but also offers an efficient means of delivering exosome-coated nanoparticles in hypoxic conditions. The self-healing properties of the hydrogel, along with its component, gelatin, aids in hemostasis, while its crosslinking bonds facilitate hydrogen peroxide decomposition, to ameliorate wound inflammation. Here, we show the potential of this multifunctional hydrogel for enhanced healing, promoting angiogenesis, facilitating exosome delivery, mitigating hypoxia, and inhibiting inflammation in a male rat full-thickness wound model. Challenges including hypoxia, inflammation, and inadequate exosome intracellular delivery hinder wound healing. Here, the authors show that a multifunctional exosome-coated oxygen nanobubble-laden hydrogel enhances exosome delivery and mitigates hypoxia for enhanced wound healing.

Hydrogels are attractive materials for tissue engineering, but efforts to date have shown limited ability to produce the microstructural features necessary to promote cellular self-organization into hierarchical three-dimensional (3D) organ models. Here we develop a hydrogel ink containing prefabricated gelatin fibres to print 3D organ-level scaffolds that recapitulate the intra- and intercellular organization of the heart. The addition of prefabricated gelatin fibres to hydrogels enables the tailoring of the ink rheology, allowing for a controlled sol–gel transition to achieve precise printing of free-standing 3D structures without additional supporting materials. Shear-induced alignment of fibres during ink extrusion provides microscale geometric cues that promote the self-organization of cultured human cardiomyocytes into anisotropic muscular tissues in vitro. The resulting 3D-printed ventricle in vitro model exhibited biomimetic anisotropic electrophysiological and contractile properties.A gelatin–alginate hydrogel ink incorporating short gelatin fibres guides the self-organization of human cardiomyocytes into contractile tissues that can be 3D-printed into structures mimicking human organs.

Bone is a highly vascularized tissue with a unique and complex structure. Long bone consists of a peripheral cortical shell containing a network of channels for vascular penetration and an inner highly vascularized bone marrow space. Bioprinting is a powerful tool to enable rapid and precise spatial patterning of cells and biomaterials. Here we developed a two-step digital light processing technique to fabricate a bone-mimetic 3D hydrogel construct based on octacalcium phosphate (OCP), spheroids of human umbilical vein endothelial cells (HUVEC), and gelatin methacrylate (GelMA) hydrogels. The bone-mimetic 3D hydrogel construct was designed to consist of a peripheral OCP-containing GelMA ring to mimic the cortical shell, and a central GelMA ring containing HUVEC spheroids to mimic the bone marrow space. We further demonstrate that OCP, which is evenly embedded in the GelMA, stimulates the osteoblastic differentiation of mesenchymal stem cells. We refined the design of a spheroid culture device to facilitate the rapid formation of a large number of HUVEC spheroids, which were embedded into different concentrations of GelMA hydrogels. It is shown that the concentration of GelMA modulates the extent of formation of the capillary-like structures originating from the HUVEC spheroids. This cell-loaded hydrogel-based bone construct with a biomimetic dual ring structure can be potentially used for bone tissue engineering.

Biomaterial wound dressings, such as hydrogels, interact with host cells to regulate tissue repair. This study investigates how crosslinking of gelatin-based hydrogels influences immune and stromal cell behavior and wound healing in female mice. We observe that softer, lightly crosslinked hydrogels promote greater cellular infiltration and result in smaller scars compared to stiffer, heavily crosslinked hydrogels. Using single-cell RNA sequencing, we further show that heavily crosslinked hydrogels increase inflammation and lead to the formation of a distinct macrophage subpopulation exhibiting signs of oxidative activity and cell fusion. Conversely, lightly crosslinked hydrogels are more readily taken up by macrophages and integrated within the tissue. The physical properties differentially affect macrophage and fibroblast interactions, with heavily crosslinked hydrogels promoting pro-fibrotic fibroblast activity that drives macrophage fusion through RANKL signaling. These findings suggest that tuning the physical properties of hydrogels can guide cellular responses and improve healing, offering insights for designing better biomaterials for wound treatment. Impaired wound healing that leads to scar remains a clinical challenge. Here, the authors study the effects of hydrogel crosslinking on cellular behavior in skin wounds and its effect on immune and stromal cell activity.

While there has been considerable success in the three-dimensional bioprinting of relatively large standalone filamentous tissues, the fabrication of solid fibers with ultrafine diameters or those cannular featuring ultrathin walls remains a particular challenge. Here, an enabling strategy for (bio)printing of solid and hollow fibers whose size ranges could be facilely adjusted across a broad spectrum, is reported, using an aqueous two-phase embedded (bio)printing approach combined with specially designed cross-linking and extrusion methods. The generation of standalone, alginate-free aqueous architectures using this aqueous two-phase strategy allowed freeform patterning of aqueous bioinks, such as those composed of gelatin methacryloyl, within the immiscible aqueous support bath of poly(ethylene oxide). Our (bio)printing strategy revealed the fabrication of standalone solid or cannular structures with diameters as small as approximately 3 or 40 μm, respectively, and wall thicknesses of hollow conduits down to as thin as <5 μm. With cellular functions also demonstrated, we anticipate the methodology to serve as a platform that may satisfy the needs for the different types of potential biomedical and other applications in the future, especially those pertaining to cannular tissues of ultrasmall diameters and ultrathin walls used toward regenerative medicine and tissue model engineering.

The data concerning the synthesis and physicochemical characteristics of one of the practically important proteins—gelatin, as well as the possibilities of its practical application, are systematized and discussed. When considering the latter, emphasis is placed on the use of gelatin in those areas of science and technology that are associated with the specifics of the spatial/molecular structure of this high-molecular compound, namely, as a binder for the silver halide photographic process, immobilized matrix systems with a nano-level organization of an immobilized substance, matrices for creating pharmaceutical/dosage forms and protein-based nanosystems. It was concluded that the use of this protein is promising in the future.