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1. Fabrication and Characterization of Quad-Component Bioinspired Hydrogels to Model Elevated Fibrin Levels in Central Nervous Tissue Scaffolds

   https://doi.org/10.3390/gels10030203  

   Diaz-Lasprilla, Ana M; McKee, Meagan; Jimenez-Vergara, Andrea C; Ravi, Swathisri; Bellamy, Devon; Ortega, Wendy; Crosby, Cody O; Steele, Jennifer; Plascencia-Villa, Germán; Perry, George; et al (March 2024, Gels)

   Kakehashi, Rie; Yamashita, Yuji (Ed.)

   Multicomponent interpenetrating polymer network (mIPN) hydrogels are promising tissue-engineering scaffolds that could closely resemble key characteristics of native tissues. The mechanical and biochemical properties of mIPNs can be finely controlled to mimic key features of target cellular microenvironments, regulating cell-matrix interactions. In this work, we fabricated hydrogels made of collagen type I (Col I), fibrin, hyaluronic acid (HA), and poly (ethylene glycol) diacrylate (PEGDA) using a network-by-network fabrication approach. With these mIPNs, we aimed to develop a biomaterial platform that supports the in vitro culture of human astrocytes and potentially serves to assess the effects of the abnormal deposition of fibrin in cortex tissue and simulate key aspects in the progression of neuroinflammation typically found in human pathologies such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and tissue trauma. Our resulting hydrogels closely resembled the complex modulus of AD human brain cortex tissue (~7.35 kPa), promoting cell spreading while allowing for the modulation of fibrin and hyaluronic acid levels. The individual networks and their microarchitecture were evaluated using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Human astrocytes were encapsulated in mIPNs, and negligible cytotoxicity was observed 24 h after the cell encapsulation. 

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2. Simultaneous One‐Pot Interpenetrating Network Formation to Expand 3D Processing Capabilities

   https://doi.org/10.1002/adma.202202261  

   Dhand, Abhishek_P; Davidson, Matthew_D; Galarraga, Jonathan_H; Qazi, Taimoor_H; Locke, Ryan_C; Mauck, Robert_L; Burdick, Jason_A (June 2022, Advanced Materials)

   Abstract The incorporation of a secondary network into traditional single‐network hydrogels can enhance mechanical properties, such as toughness and loading to failure. These features are important for many applications, including as biomedical materials; however, the processing of interpenetrating polymer network (IPN) hydrogels is often limited by their multistep fabrication procedures. Here, a one‐pot scheme for the synthesis of biopolymer IPN hydrogels mediated by the simultaneous crosslinking of two independent networks with light, namely: i) free‐radical crosslinking of methacrylate‐modified hyaluronic acid (HA) to form the primary network and ii) thiol–ene crosslinking of norbornene‐modified HA with thiolated guest–host assemblies of adamantane and β‐cyclodextrin to form the secondary network, is reported. The mechanical properties of the IPN hydrogels are tuned by changing the network composition, with high water content (≈94%) hydrogels exhibiting excellent work of fracture, tensile strength, and low hysteresis. As proof‐of‐concept, the IPN hydrogels are implemented as low‐viscosity Digital Light Processing resins to fabricate complex structures that recover shape upon loading, as well as in microfluidic devices to form deformable microparticles. Further, the IPNs are cytocompatible with cell adhesion dependent on the inclusion of adhesive peptides. Overall, the enhanced processing of these IPN hydrogels will expand their utility across applications. 

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3. Soft, strong, tough, and durable protein-based fiber hydrogels

   https://doi.org/10.1073/pnas.2213030120  

   Wang, Mingkun; Sun, Shuofei; Dong, Gening; Long, Feifei; Butcher, Jonathan T. (February 2023, Proceedings of the National Academy of Sciences)

   Load-bearing soft tissues normally show J-shaped stress–strain behaviors with high compliance at low strains yet high strength at high strains. They have high water content but are still tough and durable. By contrast, naturally derived hydrogels are weak and brittle. Although hydrogels prepared from synthetic polymers can be strong and tough, they do not have the desired bioactivity for emerging biomedical applications. Here, we present a thermomechanical approach to replicate the combinational properties of soft tissues in protein-based photocrosslinkable hydrogels. As a demonstration, we create a gelatin methacryloyl fiber hydrogel with soft tissue-like mechanical properties, such as low Young’s modulus (0.1 to 0.3 MPa), high strength (1.1 ± 0.2 MPa), high toughness (9,100 ± 2,200 J/m 3 ), and high fatigue resistance (2,300 ± 500 J/m 2 ). This hydrogel also resembles the biochemical and architectural properties of native extracellular matrix, which enables a fast formation of 3D interconnected cell meshwork inside hydrogels. The fiber architecture also regulates cellular mechanoresponse and supports cell remodeling inside hydrogels. The integration of tissue-like mechanical properties and bioactivity is highly desirable for the next-generation biomaterials and could advance emerging fields such as tissue engineering and regenerative medicine. 

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4. Design, Synthesis, and Application of a Water‐soluble Photocage for Aqueous Cyclopentadiene‐based Diels‐Alder Photoclick Chemistry in Hydrogels

   https://doi.org/10.1002/anie.202301157  

   Bailey, Sophia J.; Hopkins, Erik; Rael, Kiara D.; Hashmi, Arsalan; Urueña, Juan Manuel; Wilson, Maxwell Z.; Read de Alaniz, Javier (March 2023, Angewandte Chemie International Edition)

   Abstract Spatiotemporally functionalized hydrogels have exciting applications in tissue engineering, but their preparation often relies on radical‐based strategies that can be deleterious in biological settings. Herein, the computationally guided design, synthesis, and application of a water‐soluble cyclopentadienone‐norbornadiene (CPD‐NBD) adduct is disclosed as a diene photocage for radical‐free Diels‐Alder photopatterning. We show that this scalable CPD‐NBD derivative is readily incorporated into hydrogel formulations, providing gels that can be patterned with dienophiles upon 365 nm uncaging of cyclopentadiene. Patterning is first visualized through conjugation of cyanine dyes, then biological utility is highlighted by patterning peptides to direct cellular adhesion. Finally, the ease of use and versatility of this CPD‐NBD derivative is demonstrated by direct incorporation into a commercial 3D printing resin to enable the photopatterning of structurally complex, printed hydrogels. 

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5. Engineering Adhesive Hydrogels for Hemostasis and Vascular Repair

   https://doi.org/10.3390/polym17070959  

   Jeon, Juya; Subramani, Shri Venkatesh; Lee, Kok Zhi; Elizondo-Benedetto, Santiago; Zayed, Mohamed Adel; Zhang, Fuzhong (April 2025, Polymers)

   Adhesive hydrogels with tunable mechanical properties and strong adhesion to wet, dynamic tissues have emerged as promising materials for tissue repair, with potential applications in wound closure, hemorrhage control, and surgical adhesives. This review highlights the key design principles, material classifications, and recent advances in adhesive hydrogels designed for vascular repair. The limitations of existing adhesive hydrogels, including insufficient mechanical durability, suboptimal biocompatibility, and challenges in targeted delivery, are critically evaluated. Furthermore, innovative strategies—such as incorporating self-healing capabilities, developing stimuli-responsive systems, integrating functional nanocomposites, and employing advanced fabrication techniques like 3D bioprinting—are discussed to enhance adhesion, mechanical stability, and vascular tissue regeneration. While significant progress has been made, further research and optimization are necessary to advance these materials toward clinical translation, offering a versatile and minimally invasive alternative to traditional vascular repair techniques. 

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