The treatment of intracerebral hemorrhage (ICH) remains highly challenging, primarily due to its dynamic and multifaceted pathologies, which create a hostile microenvironment at the lesion site characterized by a ROS-inflammation-glial scar feedback loop and severely impaired neural regeneration. Herein, a dynamic protein-polysaccharide hydrogel is designed, constructed by a visible light-induced thiol-disulfide exchange reaction as a general strategy, and integrated with a spatiotemporal controlled delivery of chondroitinase ABC (ChABC) and insulin-like growth factor-1 (IGF-1) loaded in mesoporous silica nanoparticles (MSNs). Thiolated gelatin and thiolated hyaluronan were chosen to formulate the hydrogel that mimics brain ECM providing structure support with cell adhesion, infiltration, and tunable degradability, but also presents anti-swelling and pro-coagulant capacities. Importantly, the thiol-disulfide chemistry endowed the hydrogel efficient ROS scavenging and ROS-responsive on-demand release of ChABC, while MSNs loading achieved a sustained release of IGF-1. In vitro studies, the hydrogel is shown to reduce cellular ROS, regulate anti-inflammation polarization of macrophages via the MAPK signaling pathway, and promote neural stem cells (NSCs) proliferation, migration, differentiation and endothelial angiogenesis. Moreover, in an ICH mouse model, the hydrogel is demonstrated not only to enable efficient tissue ROS scavenging, anti-inflammation polarization of microglial/macrophages, and dynamical self-adaptive reduction of glial scar, achieving microenvironment remodeling, but also to regulate behaviors of endogenous NSCs and enhance angiogenesis, providing neural regeneration. Consequently, these effects enhanced neurons and myelin repair, ultimately contributing to synergistic recovery of neurological function. Overall, this dynamic hydrogel represents a promising strategy for simultanously remodeling the lesion site’s microenvironment and promoting neural regeneration, thereby improving the treatment efficacy of ICH.

Treating wounds that involve multiple types of injury is particularly challenging due to their complex morphology and the diverse mechanical properties of the affected biological tissues. Here we report a machine learning (ML)-guided rational design of bioglues, termed TuneGlues, tailored with mechanical adaptability for multitissue trauma. By leveraging ML, we establish task-oriented relationships between TuneGlues and various tissues, enabling precise optimization for specific targets. Four representative TuneGlues, which are developed and tested for lung, intestine, skin and bone injuries, demonstrate promising adhesive properties and postoperative healing outcomes. In addition, we integrate a comprehensive mechanical database derived from the ML model into a custom first-aid device capable of rapidly delivering optimized TuneGlues to target tissues. This system notably reduces the duration of wound treatment and enhances outcomes for multitissue trauma in open surgeries. The integration of ML-guided TuneGlues design with a first-aid delivery device provides a transformative strategy for emergency care, advancing the field of multitissue trauma treatment and tissue engineering.

Osteonecrosis is a devastating orthopedic disease in clinic that generally occurs in the femoral head associating with corticosteroid use up to 49 % in patients. In particular, glucocorticoids induced osteonecrosis of the femoral head is closely related to the local immune response that characterized by abnormal macrophage activation and inflammatory cell infiltration at the necrotic site, forming a pro-inflammatory microenvironment dominated by M1 macrophages, and thus leads to failure of bone repair and regeneration. Here, we report a bone regeneration strategy that constructs an immune regulatory biomaterial platform using an injectable thiolated hyaluronic acid hydrogel with lithium-doped nano-hydroxyapatite (Li-nHA@Gel) delivery for osteonecrosis treatment. Li-nHA@Gel achieved a sustain and longterm release of Li ions, which might enhance M2 macrophage polarization through the activation of the JAK1/STAT6/STAT3 signaling pathway, and the following induced pro-repair immune microenvironment mediated the enhancement of the osteogenic and angiogenic differentiation. Moreover, both in vitro and in vivo studies indicated that Li-nHA@Gel enhanced M2 macrophage polarization, osteogenesis, and angiogenesis, and thus promoted the bone and blood vessel formation. Taken together, this novel bone immunomodulatory biomaterial platform that promotes bone regeneration by enhancing M2 macrophage polarization, osteogenesis, and angiogenesis could be a promising strategy for osteonecrosis treatment.

Cavernous nerve injury (CNI), resulting in erectile dysfunction (ED), poses a significant threat to the quality of life for men. Strategies utilizing conductive hydrogels have demonstrated promising results for the treatment of peripheral nerves with a large diameter (>2 mm). However, integrating convenient minimally invasive operation, antiswelling and immunomodulatory conductive hydrogels for treating small-diameter injured cavernous nerves remains a great challenge. Here, a sprayable adhesive conductive hydrogel (GACM) composed of gelatin, adenine, carbon nanotubes, and mesaconate designed for cavernous nerve repair is developed. Multiple hydrogen bonds provide GACM with excellent adhesive and antiswelling properties, enabling it to establish a conformal electrical bridge with the damaged nerve and aiding in the regeneration process. Additionally, mesaconate-loaded GACM suppresses the release of inflammatory factors by macrophages and promotes the migration and proliferation of Schwann cells. In vivo tests demonstrate that the GACM hydrogel repairs the cavernous nerve and restores erectile function and fertility. Furthermore, the feasibility of sprayable GACM in minimally invasive robotic surgery in beagles is validated. Given the benefits of therapeutic effectiveness and clinical convenience, the research suggests a promising future for sprayable GACM materials as advanced solutions for minimally invasive nerve repair.

Chemotherapy is the primary therapy for colorectal cancer. However, its efficacy has been limited by chemoresistance, which is mainly caused by inadequate intratumoral drug accumulation and immunosuppressive microenvironments. To address these limitations, we developed a low-intensity ultrasound (LIU)-controlled and charge-reversible nanogel (R-NG), utilizing conjugated chitosan-polypyrrole polymers linked via thioketal bonds, with TiO2 absorbed onto its surface. Following the loading of oxaliplatin, the Oxa-R-NGs were ultimately synthesized. In the acidic tumor environment, the protonation of the pyrrole ring triggered the conversion of Oxa-R-NG into a positively charged form, thereby enhancing tumor penetration and cellular internalization. Based on the charge conversion, intratumoral accumulating Oxa-R-NG was triggered by LIU to continuously generate reactive oxygen species (ROS), which not only disrupted thioketal bonds to liberate oxaliplatin but also regulated tumor-associated macrophage polarization. Consequently, Oxa-R-NG boosted the chemotherapy for colorectal cancer by improving intratumoral drug accumulation and reversing the local immunosuppressive microenvironment synergistically.

The epithelium, an essential barrier to protect organisms against infection, exists in many organs. However, rapid re-epithelialization to restore tissue integrity and function in an adverse environment is challenging. In this work, a long-term anti-inflammatory and antioxidant hydrogel with mechanical stimulation for rapid re-epithelialization, mainly composed of the small molecule thioctic acid, biocompatible glycine, and γ-Fe2O3 nanoparticles is reported. Glycine-modified supramolecular thioctic acid is stable and possesses outstanding mechanical properties. The incorporating γ-Fe2O3 providing the potential contrast function for magnetic resonance imaging observation, can propel hydrogel reconfiguration to enhance the mechanical properties of the hydrogel underwater due to water-initiated release of Fe3+. In vitro experiments show that the hydrogels effectively reduced intracellular reactive oxygen species, guided macrophages toward M2 polarization, and alleviated inflammation. The effect of rapid re-epithelialization is ultimately demonstrated in a long urethral injury model in vivo, and the mechanical stimulation of hydrogels achieves effective functional replacement and ultimately accurate remodeling of the epithelium. Notably, the proposed strategy provides an advanced alternative treatment for patients in need of large-area epithelial reconstruction.

A highly efficient asymmetric (3 + 2) cycloaddition of α-diazo pyrazoleamides with silyl enol ethers was realized by employing a chiral N,N'-dioxide-Ni(II) complex catalyst. The process includes the formation of chiral nickel carbenoid intermediate and the following enantioselective cycloaddition reaction. The desired dihydrofuran O,O-acetal derivatives were obtained in good yields (up to 90%) with high enantioselectivity (up to 99% ee) under mild reaction conditions within short reaction time. On the basis of the determination of the catalyst structure, a possible transition state mode was proposed.

Ideal repair of intestinal injury requires a combination of leakage-free sealing and postoperative antiadhesion. However, neither conventional hand-sewn closures nor existing bioglues/patches can achieve such a combination. To this end, we develop a sandwiched patch composed of an inner adhesive and an outer antiadhesive layer that are topologically linked together through a reinforced interlayer. The inner adhesive layer tightly and instantly adheres to the wound sites via -NHS chemistry; the outer antiadhesive layer can inhibit cell and protein fouling based on the zwitterion structure; and the interlayer enhances the bulk resilience of the patch under excessive deformation. This complementary trilayer patch (TLP) possesses a unique combination of instant wet adhesion, high mechanical strength, and biological inertness. Both rat and pig models demonstrate that the sandwiched TLP can effectively seal intestinal injuries and inhibit undesired postoperative tissue adhesion. The study provides valuable insight into the design of multifunctional bioadhesives to enhance the treatment efficacy of intestinal injuries.

According to clinical statistics, the mortality of patients with early brainstem hemorrhage is high. In this study, we established rat models of brainstem hemorrhage by injecting type VII collagenase into the right basotegmental pontine and investigated the pathological changes of early brainstem hemorrhage using multi-sequence magnetic resonance imaging and histopathological methods. We found that brainstem hematoma gradually formed in the injured rats over the first 3 days and then reduced after 7 days. The edema that occurred was mainly of the vasogenic type. No complete myelin sheath structure was found around the focus of the brainstem hemorrhage. The integrity and continuity of nerve fibers gradually deteriorated over the first 7 days. Neuronal degeneration was mild in the first 3 days and then obviously aggravated on the 7th day. Inflammatory cytokines, interleukin-1β, and tumor necrosis factor α appeared on the 1st day after intracerebral hemorrhage, reached peak levels on the 3rd day, and decreased from the 7th day. Our findings show the characteristics of the progression of early brainstem hemorrhage.

Triply periodic minimum surfaces (TPMS), which outperform other structures in terms of bulk moduli and relative density, have been widely used to dramatically improve the mechanical strength of natural echinoderm skeletons and engineered scaffolds. Herein, TPMS‐structure‐based 3D‐printed hydroxyapatite (HAp) scaffolds to highly improve their limited mechanical strength and evaluate the underlying mechanism in terms of mechanical match and biological bone repair process as a bone regeneration scaffold are constructed. The results show that TPMS‐structure‐based HAp scaffolds have a greater compressive strength range that is sufficient to meet the strength requirements for human cortical and trabecular bone, and outperform traditional HAp scaffolds with Cross‐hatch structures in terms of compressive strength, cell density, and osteogenic differentiation. The reduction of stress concentration and open‐cell permeable structure of Split‐P scaffolds can benefit the generation and ingrowth of new bone after the in vivo implantation in the rabbit femur bone. Furthermore, RNA‐seq and immunochemistry staining results of in vivo samples unravel the bone repair mechanism in a time sequence. The optimized scaffolds with TPMS macrostructures and an in‐depth understanding of repair mechanisms will contribute to the development of bone regeneration materials that perform on par with load‐bearing bone.

Vinylcarbene insertion into the nitrogen-hydrogen (N-H) bond of amines allows direct access to α,β-unsaturated γ-amino acid derivatives, meeting a marked challenge in the control of regio- and enantioselectivities. Here, we report a highly γ-selective and enantioselective insertion into N-H bonds of aliphatic or aromatic secondary amines with vinyl substituted α-diazo pyrazoleamides using a high-spin chiral N,N'-dioxide/cobalt(II) complex catalyst. The method affords a wide variety of valuable optically active Z- and E-type vinyl γ-amino amides. Calculation reveals a spin state change from the quartet cobalt(II) complex to a doublet Co(II)-carbene species for facile Z-selective and enantioselective nucleophilic addition.

Intracerebral hemorrhage (ICH) will be accompanied by the overload of iron and reactive oxygen species (ROS) following hematoma clearance. Although deferoxamine (DFO) has been widely utilized as a clinical first-line siderophore to remove the iron overload, the ROS-inducing damage still greatly limits the therapeutic effect of DFO. To address this issue, we designed and fabricated a series of dual-functional macromolecular nanoscavengers featuring high-density DFO units and catechol moieties. Note that the former units could effectively remove the iron overload, while the latter ones could efficiently deplete the ROS. The resulting nanoscavengers efficiently down-regulate the iron and ROS levels as well as significantly reduce the cell death in both iron-overloaded RAW 264.7 cells and the ICH mice model. This work suggests a novel clue for the ICH-ameliorated iron-depleting interventional therapeutic regimen.

Organoselenium compounds, due to their high structural diversity, special function, and biological activities, have drawn attention in synthetic chemistry. Herein, a novel example of chiral N,N'-dioxide/ cobalt(II) complex catalyzed asymmetric [2,3]-sigmatropic rearrangement of allylic selenides with a-diazo pyrazoleamides is disclosed, which represents a highly efficient approach to optically active selenides bearing a quaternary C-Se stereocenter. Most of the reactions proceed with 0.5-2 mol % catalyst loading in an inert-free gas atmosphere, and a wealth of chiral selenides are obtained in up to 99% yield and 97% enantiomeric excess (ee). The control experiments demonstrate the high reactivity of allylic selenides, as well as the conspicuous superiority of chiral N,N'-dioxide ligand and a-diazo pyrazoleamide in [2,3]-sigmatropic rearrangement. The mechanism studies reveal that the key to asymmetric rearrangement of allylic selenium ylides is the transfer of chirality from the stable chiral selenium to the carbon of the product. A feasible catalytic cycle is proposed as well.

Background and Purpose Brainstem hemorrhage (BSH) is the most devastating subtype of intracerebral hemorrhage (ICH) with the highest mortality ranging from 56 % to 61.2 %. However, there is no effective medical or surgical therapy to improve its outcomes in clinic to date due to lack of understanding of its injury mechanisms. Herein, we explored the brainstem iron overload and injury in a rat model of BSH. Methods Neurological scores were examined on day 1, 3, and 7 after modeling, and mortality of the rats was recorded to draft a survival curve. Rats were monitored by MRI using T2 and susceptibility weighted imaging (SWI) before sacrifice for examination of histology and immunofluorescence on day 1, 3, and 7. Results BSH rats had a high mortality of 56 % and demonstrated the severe neurological deficits mimicking the clinical conditions. SWI showed that the same increasing tendency in change of hypointense area with that in iron deposition by Perls staining from day 1 to 7. Expression of heme oxygenase 1 (HO-1) and generation of reactive oxygen species (ROS) had similar tendency and both peaked on day 3. Neuronal degeneration occurred and stayed elevated from day 1 to 7, while myelin sheath injury was initially observed on day 1 but without significant difference within 7 days. Conclusions: The time courses of erythrocyte lysis, HO-1 expression, iron deposition and ROS generation are related to each other after BSH. Besides, brainstem injury including neuronal degeneration and myelin damage were observed and discussed.

A nickel(ii) catalyzed enantioselective thio-Claisen rearrangement of α-diazo pyrazoleamides with thioindoles was realized with modified chiral N,N'-dioxide ligands, affording a variety of C3-substituted indole derivatives in high yields (up to 95%) with excellent enantioselectivities (up to 96% ee) under mild reaction conditions. A possible transition state model was proposed based on previous reports and the X-ray crystal structure of the catalyst.

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high morbidity and mortality. However, there is no effective therapy method to improve its clinical outcomes to date. Here we report an injectable gelatin hydrogel that is capable of suppressing inflammation and enhancing functional recovery in a mouse model of ICH. Thiolated gelatin was synthesized by EDC chemistry and then the hydrogel was formed through Michael addition reaction between the thiolated gelatin and polyethylene glycol diacrylate. The hydrogel was characterized by scanning electron microscopy, porosity, rheology, and cytotoxicity before evaluating in a mouse model of ICH. The in vivo study showed that the hydrogel injection into the ICH lesion reduced the neuron loss, attenuated the neurological deficit post-operation, and decreased the activation of the microglia/macrophages and astrocytes. More importantly, the pro-inflammatory M1 microglia/macrophages polarization was suppressed while the anti-inflammatory M2 phenotype was promoted after the hydrogel injection. Besides, the hydrogel injection reduced the release of inflammatory cytokines (IL-1β and TNF-α). Moreover, integrin β1 was confirmed up-regulated around the lesion that is positively correlated with the M2 microglia/macrophages. The related mechanism was proposed and discussed. Taken together, the injectable gelatin hydrogel suppressed the inflammation which might contribute to enhance the functional recovery of the ICH mouse, making it a promising application in the clinic.

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that is associated with high morbidity and mortality. However, up to now, there are no effective prevention methods or specific therapies to improve its clinical outcomes. Herein, we explore preliminarily the efficacy of crocin, a carotenoid extracted from the stigma of saffron known for its anti-oxidation and free radical scavenging activities, in a mouse ICH model induced with collagenase infusion. Crocin or saline was administrated 6 h after ICH and then every 12 h for up to 7 days. Neurological scores were examined on days 1, 3, and 7 after ICH. Mice were sacrificed after1, 3, and 7 days of crocin treatment for examination of histology and immunohistochemistry. The results showed that oral administration of crocin attenuated the neurological deficits and reduced the myelin loss, neuron degeneration, iron deposition, reactive oxygen species (ROS) production and heme oxygenase-1 (HO-1) expression in the early stage of ICH, making it potential to be an ideal candidate for medical therapy of ICH in clinic.

Asymmetric insertion of α-diazoesters into the N–H bond of N-sp2-hybridized benzophenone imine was realized by using Rh2(esp)2 and chiral guanidine cooperative catalysis.