Advanced hydrogels based on natural macromolecules: chemical routes to achieve mechanical versatility

Advances in synthetic routes to chemically modify natural macromolecules such as polysaccharides and proteins have allowed designing functional hydrogels able to tackle current challenges in the biomedical field. Hydrogels are hydrophilic three-dimensional systems able to absorb or retain a large volume of water, prepared from a low percentage of precursor macromolecules. The typical fragile elastic structure of common hydrogel formulations often limits their usage. Three main fabrication strategies involving several compounds or multimodified materials known as double networks, dual-crosslinked networks, and interpenetrating networks have been explored to impart mechanical strength to hydrogels. Widely investigated for synthetic polymers, these approaches allow obtaining added-value hydrogels with a large spectrum of mechanical properties. Advances in the development of such hydrogels with biomacromolecules as main constituent materials have enabled the fabrication of hydrogels with improved key properties for medical use, including biocompatibility, controlled release of active substances and tailored biodegradability, while exploring sustainable sources. This review describes recent advances in the use of proteins, as well as natural and semi-synthetic polymers for the fabrication of hydrogels for biomedical applications. Structures processed via double network, dual-crosslinked, or interpenetrating network strategies are reviewed, and emphasis is given to the type of chemical modifications and reactions, as well as the covalent and non-covalent interactions/bonds involved in those mechanisms.publishe

STIM1 R304W in mice causes subgingival hair growth and an increased fraction of trabecular bone

Calcium signaling plays a central role in bone development and homeostasis. Store operated calcium entry (SOCE) is an important calcium influx pathway mediated by calcium release activated calcium (CRAC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) is an endoplasmic reticulum calcium sensing protein important for SOCE. We generated a mouse model expressing the STIM1 R304W mutation, causing Stormorken syndrome in humans. Stim1R304W/R304W mice showed perinatal lethality, and the only three animals that survived into adulthood presented with reduced growth, low body weight, and thoracic kyphosis. Radiographs revealed a reduced number of ribs in the Stim1R304W/R304W mice. Microcomputed tomography data revealed decreased cortical bone thickness and increased trabecular bone volume fraction in Stim1R304W/R304W mice, which had thinner and more compact bone compared to wild type mice. The Stim1R304W/+ mice showed an intermediate phenotype. Histological analyses showed that the Stim1R304W/R304W mice had abnormal bone architecture, with markedly increased number of trabeculae and reduced bone marrow cavity. Homozygous mice showed STIM1 positive osteocytes and osteoblasts. These findings highlight the critical role of the gain-of-function (GoF) STIM1 R304W protein in skeletal development and homeostasis in mice. Furthermore, the novel feature of bilateral subgingival hair growth on the lower incisors in the Stim1R304W/R304W mice and 25 % of the heterozygous mice indicate that the GoF STIM1 R304W protein also induces an abnormal epithelial cell fate