Abstract Cell therapy strategies hold great promise for nucleus pulposus (NP) regeneration and intervertebral disc degeneration (IVDD) treatment. However, their therapeutic efficiency is compromised by the anoikis of administered cells and the harsh environment in degenerated intervertebral discs (IVD). Inspired by the ability of nucleobases to form multiple H‐bonds, a nucleobase‐driven self‐gelling strategy is proposed for the incorporation of nucleobases (e.g., thymine) into hyaluronic acid (HA) chains to trigger gel formation through enhanced intermolecular H‐bond interactions. An aqueous solution of a thymine‐modified HA (HAT) supramolecular polymer is shown to exhibit self‐gelation behavior, injectability, tissue adhesion, and hydration capacity (comparable to that observed in the NP tissue of a 25‐year‐old adult). These characteristics enable the injection and filling of the HAT hydrogel system in the IVD, integration of the separated NP tissues, restoration of the biomechanical functions of the degenerated IVD, and securing of the encapsulated cells in the NP site. Manganese dioxide (MnO 2 ) nanoparticles incorporated into the HAT system (HATMn) regulate oxidative stress and the hypoxic microenvironment in degenerated IVD, ensuring the viability of the encapsulated cells. The 12‐week in vivo study results demonstrate that the administration of the MSCs‐laden HATMn system (HATMn‐MSCs) effectively restores the structure and function of degenerated IVD.
Abstract α‐lipoic acid (LA), a coenzyme, has proved to have excellent antioxidant and antibacterial activities; however, its intrinsic hydrophobicity and metastability of polyLA remains a major challenge for the application of LA‐based bulk materials in biomedical field. Herein, a self‐stabilized LA‐based deep eutectic supramolecular polymer ( LA‐DESP) adhesive is created by one‐step heating the mixture of LA and sodium α‐lipoate (LA‐Na) (S‐, R‐isomer, racemate) without introducing any exogenous stabilizing molecules. The underlying deep eutectic effect in LA/LA‐Na is unveiled to be originated from the multiple hydrogen bonds between polyLA and polyLA‐Na, which not only prevent polyLA depolymerization but also lower the melting point of LA‐DESP to the near body and pathological temperature. Copolymerization of LA and LA‐Na slows down the dissociation of polyLA‐Na, thus affording sustainable release of bioactive LA‐based small molecules and satisfactory antioxidant and antibacterial functions. Also, the LA‐DESP exhibits fast and tough adhesion to diverse substrates, including wet tissues, relying on its in situ curing property and rich carboxyl groups. The LA‐DESP is explored as a tissue sealant, which can well replace surgical suture to enhance the wound healing of skin incision in a rat model. The unprecedented deep eutectic effect will provide a new strategy for the development of LA‐based bioadhesives.
Abstract The cardiac fibrosis caused by excessive deposition of collagen and the fibro‐inflammatory cascade reaction severely impedes the cardiac regenerative efficiency after myocardial infarction (MI) so that the onefold treating target is far from satisfying therapeutic efficacy. Herein, a yes‐associated protein (YAP)‐suppressive nanodrug‐crosslinked self‐immunoregulatory polysaccharide injectable hydrogel is fabricated for the first time. To this end, cationic liposomes loading YAP inhibitor verteporfin (Lipo‐VP) is prepared and coated with oxidized fucoidan (OFu), a unique anti‐inflammation polysaccharide, to form anti‐fibrotic and immunoregulatory nanodrug (OFu‐Lipo‐VP). The coated fucoidan itself acts as a reactive oxygen species (ROS) scavenger and inflammation regulator, thus facilitating angiogenesis function by eliciting endogenous vascular endothelial growth factor secretion of macrophages. Then an injectable hydrogel (termed as OFu‐Lipo‐VP‐PGA) is formed through addition reaction between the aldehyde groups of OFu‐Lipo‐VP and the thiol groups of thiol‐modified poly(γ‐glutamic acid) (PGA‐SH), where the thiol groups can also aid in eliminating ROS. The acute MI models are established and the infarcted male rats are treated with this injectable OFu‐Lipo‐VP‐PGA hydrogel after MI. The outcomes at 28 days post‐surgery indicate efficient restoration of cardiac functions and attenuation of cardiac fibrosis. This study opens up a new possibility for MI treatment with immunoregulatory and antifibrotic injectable polysaccharide‐based hydrogel.
Abstract The hypoxia microenvironment post-myocardial infarction (MI) critically disturbs cellular metabolism and inflammation response, leading to scarce bioenergy supplying, prolonged inflammatory phase and high risk of cardiac fibrosis during cardiac restoration. Herein, an injectable hydrogel is prepared by Schiff base reaction between fructose-1,6-bisphosphate (FBP)-grafted carboxymethyl chitosan (CF) and oxidized dextran (OD), followed by loading fucoidan-coated baicalin (BA)-encapsulated zein nanoparticles (BFZ NPs), in which immunoregulatory and metabolism improving functions are integrally included. The grafted FBP serves to enhance glycolysis and provide more bioenergy for cardiomyocytes survival under hypoxia microenvironment, and elevating cellular antioxidant capacity via pentose phosphate pathway. OD with intrinsic anti-inflammatory effect can induce M2 polarization of macrophages to accelerate inflammatory elimination. While facing the possibility of endothelial-to-mesenchymal transition (EndoMT) caused by excessive expressed TGF-β1 secreted from M2 macrophages, BFZ NPs can target endothelia cells and intracellularly release BA to regulate the level of fatty acid oxidation, resulting in retained endothelial features and decreased risk of cardiac fibrosis. After being injecting the hydrogel into rats’ infarcted cardiac, the 28-day-post surgical outcomes demonstrate its benign effects on restoring cardiac functions and attenuating adverse left ventricular remodeling. This study shows a promising measure for MI treatment with immunoregulating and metabolism regulation comprehensively.
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