Biomaterials最新文献

The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia. The heterogeneity of hypoxia—primarily caused by limited oxygen penetration—has posed challenges. In this study, we designed a hypoxia-responsive nano-sensitizer by co-loading tirapazamine (TPZ), KP372-1, and MK-2206 in a metronidazole-modified polymeric vesicle. This nano-sensitizer relies on efficient endogenous NAD(P)H quinone oxidoreductase 1-mediated redox cycling induced by KP372-1, continuously consuming periphery oxygen and achieving evenly distributed hypoxia. Consequently, the normalized tumor microenvironment facilitates the self-amplified release and activation of TPZ without requiring deep penetration. The activated TPZ and metronidazole further sensitize radiotherapy, significantly reducing the radiation dose needed for extensive cell damage. Additionally, the coloaded MK-2206 complements inhibition of therapeutic resistance caused by Akt activation, synergistically enhancing the hypoxic chemoradiotherapy. This successful hypoxia normalization strategy not only overcomes hypoxia resistance in pancreatic cancer but also provides a potential universal approach to sensitize hypoxic tumor chemoradiotherapy by reshaping the hypoxic distribution.

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell–mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

Wearable diabetic healthcare devices have attracted great attention for real-time continuous glucose monitoring (CGM) using biofluids such as tears, sweat, saliva, and interstitial fluid via noninvasive ways. In response to the escalating global demand for CGM, these devices enable proactive management and intervention of diabetic patients with incorporated drug delivery systems (DDSs). In this context, multifunctional nanomaterials can trigger the development of innovative sensing and management platforms to facilitate real-time selective glucose monitoring with remarkable sensitivity, on-demand drug delivery, and wireless power and data transmission. The seamless integration into wearable devices ensures patient's compliance. This comprehensive review evaluates the multifaceted roles of these materials in wearable diabetic healthcare devices, comparing their glucose sensing capabilities with conventionally available glucometers and CGM devices, and finally outlines the merits, limitations, and prospects of these devices. This review would serve as a valuable resource, elucidating the intricate functions of nanomaterials for the successful development of advanced wearable devices in diabetes management.

Reactive oxygen species (ROS) that are overproduced in certain tumors can be considered an indicator of oxidative stress levels in the tissue. Here, we report a magnetic resonance imaging (MRI)-based probe capable of detecting ROS levels in the tumor microenvironment (TME) using ROS-responsive manganese ion (Mn²⁺)-chelated, biotinylated bilirubin nanoparticles (Mn@bt-BRNPs). These nanoparticles are disrupted in the presence of ROS, resulting in the release of free Mn²⁺, which induces T1-weighted MRI signal enhancement. Mn@BRNPs show more rapid and greater MRI signal enhancement in high ROS-producing A549 lung carcinoma cells compared with low ROS-producing DU145 prostate cancer cells. A pseudo three-compartment model devised for the ROS-reactive MRI probe enables mapping of the distribution and concentration of ROS within the tumor. Furthermore, doxorubicin-loaded, cancer-targeting ligand biotin-conjugated Dox/Mn@bt-BRNPs show considerable accumulation in A549 tumors and also effectively inhibit tumor growth without causing body weight loss, suggesting their usefulness as a new theranostic agent. Collectively, these findings suggest that Mn@bt-BRNPs could be used as an imaging probe capable of detecting ROS levels and monitoring drug delivery in the TME with potential applicability to other inflammatory diseases.

Nondestructive penetration of the blood-brain barrier (BBB) to specifically prevent iron deposition and the generation of reactive oxygen species (ROS) shows great potential for treating Parkinson's disease (PD). However, effective agents with distinct mechanisms of action remain scarce. Herein, a N-doping carbon dot (CD) emitting red light was prepared, which can sacrifice ROS and produce nitric oxide (NO) owing to its surface N-involved groups conjugated to the sp²-hybrided π-system. Meanwhile, CD can chelate iron ions, thus depressing the catalytic Fe cycle and *OH detaching to inhibit the Fenton reaction. By modifying lactoferrin (Lf) via polyethylene glycol (PEG), the resulting CD-PEG-Lf (CPL) can nondestructively cross the BBB, targeting the dopaminergic neurons via both NO-mediated reversible BBB opening and Lf receptor-mediated transportation. Accordingly, it can serve as an antioxidant, reducing oxidative stress via its unique iron chelation, free radical sacrificing, and synergy with iron reflux prevention originating from Lf. Thus, it can significantly reduce brain inflammation and improve the behavioral performance of PD mice. Additionally, CPL can image the PD via its red fluorescence. Finally, this platform can be metabolized out of the brain through cerebrospinal fluid circulation without causing obvious side effects, promising a robust treatment for PD.

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable clinical challenge due to its intricate microenvironment characterized by desmoplasia and complex tumor-stroma interactions. Conventional models hinder studying cellular crosstalk for therapeutic development. To recapitulate key features of PDAC masses, this study creates a novel sea-and-island PDAC tumor construct (s&i PTC). The s&i PTC consists of 3D-printed islands of human PDAC cells positioned within an interstitial extracellular matrix (ECM) populated by human cancer-associated fibroblasts (CAFs). This design closely mimics the in vivo desmoplastic architecture and nutrient-poor conditions. The model enables studying dynamic tumor-stroma crosstalk and signaling reciprocity, revealing both known and yet-to-be-discovered multicellular metabolic adaptations. Using the model, we discovered the orchestrated dynamic alterations of CAFs under nutrient stress, resembling critical in vivo human tumor niches, such as the secretion of pro-tumoral inflammatory factors. Additionally, nutrient scarcity induces dynamic alterations in the ECM composition and exacerbates poor cancer cell differentiation—features well-established in PDAC progression. Proteomic analysis unveiled the enrichment of proteins associated with aggressive tumor behavior and ECM remodeling in response to poor nutritional conditions, mimicking the metabolic stresses experienced by avascular pancreatic tumor cores. Importantly, the model's relevance to patient outcomes is evident through an inverse correlation between biomarker expression patterns in the s&i PTCs and PDAC patient survival rates. Key findings include upregulated MMPs and key ECM proteins (such as collagen 11 and TGFβ) under nutrient-avid conditions, known to be regulated by CAFs, alongside the concomitant reduction in E-cadherin expression associated with a poorly differentiated PDAC state under nutrient deprivation. Furthermore, elevated levels of hyaluronic acid (HA) and integrins in response to nutrient deprivation underscore the model's fidelity to the PDAC microenvironment. We also observed increased IL-6 and reduced α-SMA expression under poor nutritional conditions, suggesting a transition of CAFs from myofibroblastic to inflammatory phenotypes under a nutrient stress akin to in vivo niches. In conclusion, the s&i PTC represents a significant advancement in engineering clinically relevant 3D models of PDAC masses. It offers a promising platform for elucidating tumor-stroma interactions and guiding future therapeutic strategies to improve patient outcomes.

The proliferation of medical wearables necessitates the development of novel electrodes for cutaneous electrophysiology. In this work, poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) is combined with a deep eutectic solvent (DES) and polyethylene glycol diacrylate (PEGDA) to develop printable and biocompatible electrodes for long-term cutaneous electrophysiology recordings. The impact of printing parameters on the conducting properties, morphological characteristics, mechanical stability and biocompatibility of the material were investigated. The optimised eutectogel formulations were fabricated in four different patterns —flat, pyramidal, striped and wavy— to explore the influence of electrode geometry on skin conformability and mechanical contact. These electrodes were employed for impedance and forearm EMG measurements. Furthermore, arrays of twenty electrodes were embedded into a textile and used to generate body surface potential maps (BSPMs) of the forearm, where different finger movements were recorded and analysed. Finally, BSPMs for three different letters (B, I, O) in sign-language were recorded and used to train a logistic regressor classifier able to reliably identify each letter. This novel cutaneous electrode fabrication approach offers new opportunities for long-term electrophysiological recordings, online sign-language translation and brain-machine interfaces.

Photobiomodulation (PBM), the use of biocompatible tissue-penetrating light to interact with intracellular chromophores to modulate the fates of cells and tissues, has emerged as a promising non-invasive approach to enhancing tissue regeneration. Unlike photodynamic or photothermal therapies that require the use of photothermal agents or photosensitizers, PBM treatment does not need external agents. With its non-harmful nature, PBM has demonstrated efficacy in enhancing molecular secretions and cellular functions relevant to tissue regeneration. The utilization of low-level light from various sources in PBM targets cytochrome c oxidase, leading to increased synthesis of adenosine triphosphate, induction of growth factor secretion, activation of signaling pathways, and promotion of direct or indirect gene expression. When integrated with stem cell populations, bioactive molecules or nanoparticles, or biomaterial scaffolds, PBM proves effective in significantly improving tissue regeneration. This review consolidates findings from in vitro, in vivo, and human clinical outcomes of both PBM alone and PBM-combined therapies in tissue regeneration applications. It encompasses the background of PBM invention, optimization of PBM parameters (such as wavelength, irradiation, and exposure time), and understanding of the mechanisms for PBM to enhance tissue regeneration. The comprehensive exploration concludes with insights into future directions and perspectives for the tissue regeneration applications of PBM.

Photodynamic therapy (PDT) is a promising modality for cancer treatment. However, limited tissue penetration of external radiation and complicated tumor microenvironments (TMEs) restrict the antitumor efficiency of PDT. Herein, we report an energy-storing DNA-based hydrogel, which enables tumor-selective PDT without external radiation and regulates TMEs to achieve boosted PDT-mediated tumor immunotherapy. The system is constructed with two ultralong single-stranded DNA chains, which programmed partial complementary sequences and repeated G-quadruplex forming AS1411 aptamer for photosensitizer loading via hydrophobic interactions and π-π stacking. Then, energy-storing persistent luminescent nanoparticles are incorporated to sensitize PDT selectively at tumor site without external irradiation, generating tumor antigen to agitate antitumor immune response. The system catalytically generates O₂ to alleviate hypoxia and releases inhibitors to reverse the IDO-related immunosuppression, synergistically remodeling the TMEs. In the mouse model of breast cancer, this hydrogel shows a remarkable tumor suppression rate of 78.3 %. Our study represents a new paradigm of photodynamic immunotherapy against cancer by combining laser-free fashion and TMEs remodeling.

Dysfunction of the central nervous system (CNS) following traumatic brain injuries (TBI), spinal cord injuries (SCI), or strokes remains challenging to address using existing medications and cell-based therapies. Although therapeutic cell administration, such as stem cells and neuronal progenitor cells (NPCs), have shown promise in regenerative properties, they have failed to provide substantial benefits. However, the development of living cortical tissue engineered grafts, created by encapsulating these cells within an extracellular matrix (ECM) mimetic hydrogel scaffold, presents a promising functional replacement for damaged cortex in cases of stroke, SCI, and TBI. These grafts facilitate neural network repair and regeneration following CNS injuries. Given that natural glycosaminoglycans (GAGs) are a major constituent of the CNS, GAG-based hydrogels hold potential for the next generation of CNS healing therapies and in vitro modeling of CNS diseases. Brain-specific GAGs not only offer structural and biochemical signaling support to encapsulated neural cells but also modulate the inflammatory response in lesioned brain tissue, facilitating host integration and regeneration. This review briefly discusses different roles of GAGs and their related proteoglycan counterparts in healthy and diseases brain and explores current trends and advancements in GAG-based biomaterials for treating CNS injuries and modeling diseases. Additionally, it examines injectable, 3D bioprintable, and conductive GAG-based scaffolds, highlighting their clinical potential for in vitro modeling of patient-specific neural dysfunction and their ability to enhance CNS regeneration and repair following CNS injury in vivo.