Advanced Healthcare Materials最新文献

Despite remarkable advancements in hydrogel-based medical applications in recent years, their clinical translation for pancreatic fistula management remains challenging owing to the moist surgical environment and complex post-pancreatectomy pathophysiology. To address the clinical need for reliable wet-adhesion materials to prevent postoperative pancreatic fistula after distal pancreatectomy (DP-POPF) and postoperative adhesive intestinal obstruction, we developed an asymmetric bilayer hydrogel (BH) patch that integrates an adhesive pancreatic layer (APL) and an anti-adhesion layer (AAL). The APL combines N-hydroxysuccinimide-mediated covalent bonding with xanthan gum-driven interfacial dehydration for robust wet-tissue adhesion, the AAL, composed of poly(sulfobetaine methacrylate)-carboxymethyl chitosan, prevents fibrosis via surface hydration; the BH hydrogel incorporates Ceffe, a cell-free fat extract possessing anti-inflammatory and proangiogenic properties. The BH patch exhibits exceptional mechanical strength, prolonged post-swelling adhesion retention, and enzymatic resistance. In vitro and in vivo studies confirm its outstanding biocompatibility, antibacterial efficacy, and adhesion prevention in rat models. In a DP rat model, the Ceffe@BH group displayed significantly reduced POPF incidence versus the normal saline and hand-sewn anastomosis groups, as demonstrated by reduced drain fluid amylase, attenuated inflammation (↓TNF-α/IL-6), enhanced angiogenesis, and effective adhesion prevention. This suture-free, multifunctional hydrogel presents a standardized solution for POPF with broad potential for wet-tissue surgical applications.

Monitoring wound healing requires the development of multiplexed sensors with remote readout. Here, we report fluorescent polymeric nanofibers and nanorods as ratiometric sensors of two important physiological parameters: pH and oxygen. These nanofibers operate by dual Forster resonance energy transfer (FRET) between large number of energy donor dyes (reference) and limited number of two distinct energy acceptors sensitive to these two analytes. This configuration ensures signal amplification of analyte-sensitive energy acceptor by light-harvesting principle. The oxygen sensor is based on encapsulation of cationic donor dyes (cyanine or rhodamine derivatives) with bulky hydrophobic counterions as FRET donors and Pt-porphyrins as energy acceptors inside the nanofibers. In the pH sensor, nanofibers loaded with donor dyes are functionalized at the surface with the rhodamine-derived energy acceptor, which ensures sensitivity to pH. The developed nanosensors show ratiometric response to the analytes by changing the intensity ratio of the analyte-sensitive acceptor vs the reference donor dye. Finally, a multiplexing device combining oxygen- and pH-sensing modalities is developed, which enable sensing both pH and oxygen in a wound model by recording its emission in the red, green, and blue channels. The obtained materials will find numerous biomedical applications, including monitoring wound healing, compatible with simple smartphone-based detection.

Magnetic hyperthermia therapy (MHT) is a promising cancer treatment that has demonstrated efficacy in phase I and II clinical trials for glioblastoma and prostate cancer. MHT relies on heat generated by magnetic nanoparticles (MNPs) when exposed to alternating magnetic fields (AMFs). The heat output depends not only on the intrinsic properties of MNPs but also on extrinsic factors such as the extracellular and intracellular environments. Aggregation of MNPs under certain conditions can significantly reduce therapeutic efficiency. To overcome this limitation, we present a strategy to enhance MHT by modulating MNP-cell interactions. We functionalized dimercaptosuccinic acid (DMSA)-coated MNPs with the 92R antibody (DMSA-MNPs@92R), which selectively binds to the low-internalization chemokine receptor CCR9, overexpressed in certain tumors. Exposure of CCR9⁺ MOLT-4 cells to DMSA-MNPs@92R under AMFs resulted in enhanced tumor cell death. Our approach enables spatially controlled binding, maintaining MNPs in a less-aggregated state and at an optimal distance from the cell membrane to maximize heat generation. Mechanistic analysis confirmed that cytotoxicity is driven by localized hyperthermia at the subcellular level rather than a macroscopic temperature increase. These findings underscore the potential of controlled MNPs-cell interactions to improve in vitro MHT performance and open an interesting avenue for enhancing therapeutic efficacy.

Although antibody-drug conjugates (ADCs) are a widely used platform for developing various anticancer immunotherapeutics, the use of cancer non-selective chemicals is recognized as a drawback of ADC development. To address the issues regarding the safety and manufacturing complexity of ADCs, this study conceptualizes a single-protein platform, named dual-targeting anticancer therapeutics (DTAT), that links a cancer cell-selective cytotoxic peptide to an antibody via a linker peptide cleavable on cancer cells. As a model molecule for preclinical proof of the concept, an anti-Her2 single-chain variable fragment (scFv)-based DTAT protein named DTAT-D311 is established, which contains a recently developed anticancer peptide, herein named CPTin, as its cell-penetrating payload. This recombinant single protein efficiently induces the apoptotic death of cancer cells, which is characterized by a very early onset. In terms of in vivo efficacy in suppressing tumor growth, DTAT-D311 outperforms the anti-Her2 therapeutic antibody, trastuzumab (Herceptin). By targeting an intracellularly addictive oncoprotein, CP2c, CPTin exhibits broad-spectrum anticancer activity. In conclusion, this study demonstrates that DTAT provides an innovative pharmaceutical modality to target both a tumor surface antigen and an intracellular oncoprotein. In addition, DTAT-D311 is suggested to be a promising biopharmaceutical agent for targeted immunotherapy against Her2-positive cancers, exhibiting favorable safety profile.

Advanced skin models are critical for pursuing non-animal approaches in drug and cosmetic testing. However, existing 3D models remain complex and time-consuming, which limits their adoption. Spherical skin model (SSM) is presented, a platform that balances biological fidelity with experimental robustness. The SSM is based on a core-shell structure where the dermal core is modeled by embedding human fibroblasts into collagen microcarriers (150  $\mu m$ ), while the epidermal shell is formed by outer layers of immortalized keratinocytes. The collagen beads are generated using droplet microfluidics to enable rapid and reproducible production. The biological relevance of SSM is revealed through elevated expression of epidermal differentiation markers (loricrin, involucrin, keratin 1, keratin 10) and the dermal-epidermal junction marker collagen VII. The barrier function is validated by permeability assays that show strong exclusion of fluorescent dextran above 4 kDa. Moreover, their usefulness for screening is shown by identifying a dose-dependent effect of vitamins in reducing oxidative stress and apoptosis against tert-butyl hydroperoxide. As such, this 3D microphysiological model recapitulates key structural, molecular, and functional features of human skin while offering rapid generation, scalability, and compatibility with high-throughput applications in dermatological and cosmetic research.

Patient-derived cancer organoids have emerged as a promising in vitro model for fundamental cancer research and drug screening for therapeutic cancer treatment. Yet, while the inherent acidification of the tumor environment in vivo is controlled at a particular level, hydrogel scaffolds used for organoid culture lack this ability and their pH falls outside the physiologically relevant range. The excessive acidification can also lead to the degradation of pH-sensitive hydrogel scaffolds during long-term organoid culture, thus changing the mechanical properties of the organoid microenvironment. Here, we report a biomimetic fibrous hydrogel with built-in buffering capacity, which enables control of the local acidification of the organoid environment to maintain its mechanical and structural stability. The hydrogel is formed from aldehyde-functionalized cellulose nanocrystals carrying histidine buffering molecules, and gelatin. During long-term organoid culture, the hydrogel maintained the pH in the physiologically relevant range, while maintaining network integrity and mechanical properties. The organoids grown in this hydrogel exhibited enhanced proliferative activity of cancer cells, thus reflecting a more homeostatic tumor-like niche. This work shows that introducing a buffering functionality into the hydrogel scaffold enables significantly improved support for long-term culture of patient-derived breast cancer organoids under physiologically relevant conditions.

Fungal keratitis (FK) is an extremely blinding infectious ocular surface disease. Clinically, there are three major challenges in the topic drug treatment of FK: poor corneal permeability, poor antifungal effect, and inability to simultaneously reduce the inflammation accompanying the infection. In this work, atomically dispersed Cu-N₄ and Cu nanoclusters is designed loaded on the a small-sized positively charged CDs (denoted as Cu-SA/NC@CDs) is designed to fabricate Cu-Needs. The Cu-Needs exhibited excellent corneal permeability, which could can temporarily open the tight connections between corneal cells. More importantly, Cu-Needs achieve rapid fungal elimination and eradication through energy depletion in fungus in the early stage of FK. Subsequently, Cu-Needs effectively eliminated ROS and alleviated the inflammation in cornea tissue. This work proposes a strategy for the whole-process intervention of fungal keratitis by regulating the microenvironment of single-atom centers and nanoclusters through a tandem effect and enhancing catalytic activity. Conclusively, the excellent biosafety (biocompatibility, irritancy, ocular local toxicity and systemic toxicity) made Cu-Needs a great potential strategy in clinical treatment of FK and other serious infectious diseases.

Lower back pain is closely associated with intervertebral disc (IVD) degeneration and is a leading cause of global disability. Existing treatment options are unable to provide suitable long-term outcomes, and emerging strategies employing injectable biomaterials are hindered by factors including limited native tissue integration and depth- or time-constrained gelation mechanisms. To overcome these issues, the present research evaluates a new concept employing ultrasound to remotely trigger in situ implant formation. The concept centers around an implant precursor biomaterial consisting of an anionic polysaccharide solution containing thermally sensitive liposomes loaded with ionic crosslinkers. Ultrasound-mediated heating to 4-5 °C above normal body temperature triggers liposomal release of the crosslinking species, thereby initiating hydrogel formation. Optimization studies define the implant precursor material (1.5% wt/v sodium alginate seeded with calcium-loaded liposomes (10-15 mm calcium chloride) and 6% wt/v glass microspheres) and the ultrasound parameters (0.95 MHz, 1.6 MPa amplitude, 87% duty cycle). Proof-of-concept experiments in degenerated ex vivo bovine IVDs indicate partial restoration of biomechanical function, with the implanted biomaterial well-integrated into the disc tissue and without material herniation. These results offer promise for treating intervertebral disc degeneration, with continued refinement of biomaterials and protocols being essential for achieving robust in-disc efficacy.

Clinical therapy of multidrug-resistant (MDR) Gram-negative (GN) ESKAPE pathogens-induced pneumonia remains a serious challenge. Antimicrobial proteins (AMPs) are a promising alternative for treating MDR bacterial infections, but their effectiveness is limited by instability, narrow-spectrum activity, and poor pharmacokinetics. Although conjugated or complexed cationic polymers can enhance the antimicrobial spectrum and potency of AMPs, they also cause AMPs to interact excessively with biomacromolecules in vivo, potentially reducing their therapeutic efficacy. Herein, screening of an ultra-acid-sensitive diblock copolymer-lysozyme conjugate to self-assemble into LPOBE micelle with enhanced stability. In acidic conditions, protonated LPOBE with low positive charge showed great serum protein-nonfouling ability and yielded highly effective bactericidal activity, achieving a 99.9% reduction in three MDR GN ESKAPE strains. Inhalation delivery can achieve high local concentrations of AMPs, but mucus in the lower respiratory tract impedes their penetration into infected areas due to the positive charge of AMPs. Furthermore, bacterial pneumonia is often accompanied by excessive inflammation. Therefore, we further developed a 'One-Stone-Two-Birds' strategy by loading sodium butyrate (NaBu), a small molecule immunomodulator, to form negatively charged LPOBEN, which improves both mucus penetration and anti-inflammatory effects of LPOBE. This system offers a novel theoretical foundation to develop high-performance AMP-based nanomedicines for clinical therapy.

Peroxynitrite (ONOO^-), as the most active species of nitrogen oxides, shows the powerful potential in treating "cold" tumors. Currently, the in vivo generating efficiency of ONOO^- and triggering lethal pattern against tumor cells are the greatest challenges. Herein, an ingenious ONOO^- generator (DBTG) is first synthesized by covalently linking reactive oxygen species donor (Nile blue derivative) and nitric oxide donor (arginine analog) in a single molecule to improve production of ONOO^-. Lysosome-targeted DBTG is demonstrated to rapidly generate ONOO^- to induce lysosomal membrane permeabilization and simultaneously trigger pyroptosis and cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway of tumor cells, dramatically promoting the infiltration of T cells and NK cells, and converting "cold" tumors into "hot" tumors. In vitro and in vivo experiments show that DBTG possesses significant anti-tumor efficacy, which not only provides a template for the design of novel drug molecules but also an effective strategy for the reversal of immunosuppressive microenvironment by the powerful inflammation triggered by pyroptosis and the STING pathways.