Injectable hyaluronic acid (HA)-based hydrogels compose a promising class of materials for tissue engineering and regenerative medicine applications. However, their limited mechanical properties restrict the potential range of application. In this study, cellulose nanocrystals (CNCs) were employed as nanofillers in a fully biobased strategy for the production of reinforced HA nanocomposite hydrogels. Herein we report the development of a new class of injectable hydrogels composed of adipic acid dihydrazide-modified HA (ADH-HA) and aldehyde-modified HA (a-HA) reinforced with varying contents of aldehyde-modified CNCs (a-CNCs). The obtained hydrogels were characterized in terms of internal morphology, mechanical properties, swelling, and degradation behavior in the presence of hyaluronidase. Our findings suggest that the incorporation of a-CNCs in the hydrogel resulted in a more organized and compact network structure and led to stiffer hydrogels (maximum storage modulus, E', of 152.4 kPa for 0.25 wt % a-CNCs content) with improvements of E' up to 135% in comparison to unfilled hydrogels. In general, increased amounts of a-CNCs led to lower equilibrium swelling ratios and higher resistance to degradation. The biological performance of the developed nanocomposites was assessed toward human adipose derived stem cells (hASCs). HA-CNCs nanocomposite hydrogels exhibited preferential cell supportive properties in in vitro culture conditions due to higher structural integrity and potential interaction of microenvironmental cues with CNC's sulfate groups. hASCs encapsulated in HA-CNCs hydrogels demonstrated the ability to spread within the volume of gels and exhibited pronounced proliferative activity. Together, these results demonstrate that the proposed strategy is a valuable toolbox for fine-tuning the structural, biomechanical, and biochemical properties of injectable HA hydrogels, expanding their potential range of application in the biomedical field.

Interest in astroglial cells is rising due to recent findings supporting dynamic neuron-astrocyte interactions. There is increasing evidence of astrocytic dysfunction in several brain disorders such as depression, schizophrenia or bipolar disorder; importantly these pathologies are characterized by the involvement of the prefrontal cortex and by significant cognitive impairments. Here, to model astrocyte pathology, we injected animals with the astrocyte specific toxin L-α-aminoadipate (L-AA) in the medial prefrontal cortex (mPFC); a behavioral and structural characterization two and six days after the injection was performed. Behavioral data shows that the astrocyte pathology in the mPFC affects the attentional set-shifting, the working memory and the reversal learning functions. Histological analysis of brain sections of the L-AA-injected animals revealed a pronounced loss of astrocytes in the targeted region. Interestingly, analysis of neurons in the lesion sites showed a progressive neuronal loss that was accompanied with dendritic atrophy in the surviving neurons. These results suggest that the L-AA-induced astrocytic loss in the mPFC triggers subsequent neuronal damage leading to cognitive impairment in tasks depending on the integrity of this brain region. These findings are of relevance to better understand the pathophysiological mechanisms underlying disorders that involve astrocytic loss/dysfunction in the PFC.

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A glass-reinforced hydroxyapatite (HA) composite, recently registered as Bonelike®, was developed for bone grafting. This biomaterial is composed of a modified HA matrix with α- and β-tricalcium phosphate secondary phases and ionic species that mimic the chemical composition of human bone. Several in vitro and in vivo studies have confirmed the benefits of these properties. However, these studies were all executed with Bonelike® polygonal granules obtained by crushing. In this study, Bonelike® pellets were produced through a patented process, which required the use of techniques such as extrusion and spheronization. The final product presented a homogeneous size, a 55.1% global porosity and a spherical shape. This spherical shape permitted a better adaptation to the implantation site and improved injectability. Additionally, it also may contribute to formation of macropores as pellets packaging leaves open spaces. After implantation of Bonelike® polygonal granules and Bonelike® pellets in monocortical defects in sheep for 8 and 12 weeks, light microscopy and scanning electron microscopy showed extensive osteointegration simultaneously with bone regeneration for both presentations. Histomorphometric analysis did not reveal statistically significant differences between defects treated with Bonelike® polygonal granules and Bonelike® pellets, which suggests similar in vivo performances.

Forkhead box O transcription factors (FOXOs) regulate several signaling pathways and play crucial roles in health and disease. FOXOs are key regulators of the expression of genes involved in multiple cellular processes and their deregulation has been implicated in cancer. FOXOs are generally considered tumor suppressors and evidence also suggests that they may have a role in the regulation of cancer metabolism and angiogenesis. In order to continue growing and proliferating, tumor cells have to reprogram their metabolism and induce angiogenesis. Angiogenesis refers to the process of new blood capillary formation from pre-existing vessels, which is an essential driving force in cancer progression and metastasis through supplying tumor cells with oxygen and nutrients. This review summarizes the roles of FOXOs in the regulation of cancer metabolism and angiogenesis. A deeper knowledge of the involvement of FOXOs in these two key processes involved in cancer dissemination may help to develop novel therapeutic approaches for cancer treatment.