ACS Biomaterials Science & Engineering最新文献

Living Therapeutic Materials represent a promising technology to tackle therapeutic problems that classical materials cannot address. Despite the advancements on new functions of these devices, new applications, and new fabrication methods, the preclinical evaluation of Living Therapeutic Materials is still very limited and new challenges appear when incorporating the living devices in contact with the host. This is a critical bottleneck in the path to translation to the clinic. Therefore, we have compiled the literature on Living Therapeutic Materials, with a focus on microorganism-based living therapeutic materials, and summarized the investigations carried out to assess their biocompatibility, safety, and efficacy. We have split the investigations in three parts: in vitro, ex vivo, and in vivo assessments, where we describe common practices and remaining challenges.

Backgrounds: The buildup of reactive oxygen species (ROS) in infected wounds triggers an excessive inflammatory response, while the overuse of antibiotics has contributed to increased bacterial resistance. Therefore, developing wound dressings that effectively eliminate ROS and inhibit bacterial growth is crucial. Methods: Inspired by mussel-derived proteins, we developed a polydopamine (PDA)-grafted MXene (PDA@MXene) and 3,4-dihydroxyphenylalanine-PonG1 (DOPA-PonG1)-modified photosensitive poly(vinyl alcohol) (PVA) hydrogel as a wound dressing. PDA@MXene was synthesized through dopamine self-polymerization on the MXene surface, while tyrosine hydroxylation was used to introduce DOPA into the antibacterial peptide ponericin G1 (PonG1). The hydrogel and its components were characterized, and their morphology was examined. The hydrogel’s hemostatic ability, mechanical properties, and conductivity were evaluated. In vitro studies systematically evaluated antioxidative effects, antibacterial activity, biocompatibility, and expression of tissue regeneration–related factors. An infected full-thickness skin defect model was established in vivo, and different hydrogel treatments were applied. The wound-healing rate was then measured, followed by histological analysis using hematoxylin and eosin, Masson, Sirius Red, and immunofluorescence staining to investigate the healing mechanism. Results: The DOPA sequence enhanced PonG1 stability on the hydrogel surface, leading to sustained antibacterial ability. PDA@MXene significantly improved the hydrogel’s conductivity and mechanical strength. Notably, the combined effects of DOPA-PonG1 and PDA@MXene contributed to enhanced antibacterial and ROS-scavenging properties. In vivo findings demonstrated that the DOPA-PonG1/PDA@MXene/PVA hydrogel accelerated infected wound healing by promoting angiogenesis and collagen deposition while reducing excessive inflammation. This study presents an innovative approach for treating infected wound defects and holds promise for clinical applications.

Bone tissue engineering plays a critical role in overcoming the limitations of traditional bone grafts and implants by enhancing bone integration and regeneration. In this study, we developed a novel membrane scaffold comprising poly(ether sulfone) (PES), poly(vinyl alcohol) (PVA), and magnesium-doped carbon quantum dots (CQDs.Mg) for potential bone tissue engineering applications. Four distinct scaffold formulations (PE-CM0, PE-CM2, PE-CM3, and PE-CM4) were developed using a film applicator machine. The morphology and porosity of the scaffolds, characterized via scanning electron microscopy (SEM), revealed increased porosity with higher CQDs.Mg content. Fourier transform infrared spectroscopy (FTIR) confirmed the successful integration of functional groups from each component. Water contact angle (WCA) measurements indicated improved hydrophilicity with the addition of CQDs.Mg, which is beneficial for cell attachment and proliferation. Mechanical testing demonstrated that the scaffolds maintained adequate tensile strength and flexibility, with PE-CM3 and PE-CM4 exhibiting superior properties. Swelling assays indicated enhanced water absorption with increased CQDs.Mg content, while 14-day degradation studies showed excellent structural stability. Biocompatibility was also assessed using L929 and NIH3T3 cell lines, with cytotoxicity assays demonstrating nearly 100% cell viability across all samples. These findings suggest that the PES/PVA/CQDs.Mg scaffolds exhibit a promising combination of mechanical robustness, hydrophilicity, and biocompatibility, making them strong candidates for bone tissue engineering applications.

In the domain of tissue engineering and regenerative medicine, artificial replacements have been developed as viable options for esophageal reconstruction and serve as alternatives to traditional surgical procedures. Restoration of smooth muscle functionality is crucial in esophageal regeneration. We evaluated the efficacy of esophageal reconstructions in an animal model, using tissue-engineered films with a leaf-stacked structure (FLSS), seeded with mesenchymal stem cells (MSCs), which were genetically modified with myogenic genes. Esophageal partial defects were variously reconstructed in animals (n = 8 per group, except the no-implantation group), categorized as (1) normal rats; (2) rats implanted with naked FLSS; (3) rats implanted with FLSS with MSCs; (4) rats implanted using FLSS with myogenesis-inducing gene transfected MSCs; and (5) rats without implantation at the defect site (n = 3). The FLSS exhibited appropriate mechanical characteristics for transplantation. Successful repair of esophageal defects was observed with significantly enhanced epithelial regeneration in the MSC-seeded FLSS group compared to that in the naked FLSS group. Moreover, smooth muscle regeneration was notably higher in the FLSS with myogenesis-inducing gene transfected MSCs than in the group without myogenic gene transfection. The myogenesis-inducing gene-transfected MSC-seeded FLSS group showed a tendency toward increased smooth muscle regeneration, this indicates that FLSS with myogenesis-inducing genes transfected MSC may contribute positively to the maintenance of function in the reconstructed esophagus.

Various immunotherapeutic strategies are being developed to fight cancer, which is one of the leading causes of mortality. Dendritic cells (DCs), being professional antigen-presenting cells, after efficient manipulation with tumor-associated antigens, can lead to effective T-cell recruitment and activation at the tumor site, resulting in cytotoxic T-cell-mediated cancer cell killing. To circumvent the inefficiencies of ex vivo DC modification and patient infusion, an alternative strategy involving in situ DC activation has been explored here. Here, the vaccine components are tumor lysates, as antigens, and polyinosinic:polycytidylic acid (poly(I:C)), a toll-like receptor-3 (TLR3) agonist, as an adjuvant. Our in vitro studies demonstrate that complexing poly(I:C) with a carrier molecule, chitosan, enhances its stability and accessibility to TLR3 in the DC endosomal membrane. Material-based localized delivery of immunomodulatory factors is known to improve their stability and reduce their off-target side effects. Here, PEGDA-PLL-based macroporous scaffolds allow easy recruitment of host cells, thereby enabling effective interaction between the vaccine components loaded on them and the infiltrating immune cells. The vaccine components present in the scaffold facilitate efficient DC activation and migration, leading to subsequent T-cell activation and antitumor response, as shown by our in vivo studies.

Biofabrication and three-dimensional (3D) bioprinting enable precise spatial arrangement of cells within biomaterial scaffolds. We developed an alginate-based and Förster resonance energy transfer (FRET)-responsive "turn-on" reporter ink platform to enable real-time monitoring of matrix metalloproteinase (MMP) activity. Three distinct MMP-cleavable turn-on peptide reporters were synthesized and characterized for their cell-specific cleavage profiles using recombinant MMPs, cell-derived media, and different cell cultures (NIH3T3, HEK293, and MelHo). All turn-on reporters were covalently and site-specifically incorporated into alginate dialdehyde (ADA) to yield an MMP reporter ink. The ADA reporter ink with an MMP 13 turn-on reporter was responsive to all tested cell types over time within the cast bulk constructs. The ADA reporter ink material blended with gelatin had comparable print resolution and structural fidelity as observed for ADA. The extrusion-based bioprinted MelHo cell grids, measuring 2 × 2 cm² and containing 1 × 10⁶ cells/mL, exhibited MMP activity responses comparable to those of the casted reporter ink system, with a 3-fold increase observed at 24 h. This study introduces a versatile, FRET-based alginate bioink platform for the real-time monitoring of MMP activities, expanding the toolkit to understand cellular performance in bioprinted 3D constructs.

Cancer is one of the leading causes of mortality worldwide. Nanomedicines have significantly improved life expectancy and survival rates for cancer patients in current standard care. However, recurrence of cancer due to metastasis remains a significant challenge. Vaccines can provide long-term protection and are ideal for preventing bacterial and viral infections. Cancer vaccines, however, have shown limited therapeutic efficacy and raised safety concerns despite extensive research. Cancer vaccines target and stimulate responses against tumor-specific antigens and have demonstrated great potential for cancer treatment in preclinical studies. However, tumor-associated immunosuppression and immune tolerance driven by immunoediting pose significant challenges for vaccine design. In situ vaccination represents an alternative approach to traditional cancer vaccines. This strategy involves the intratumoral administration of immunostimulants to modulate the growth and differentiation of innate immune cells, such as dendritic cells, macrophages, and neutrophils, and restore T-cell activity. Currently approved in situ vaccines, such as T-VEC, have demonstrated clinical promise, while ongoing clinical trials continue to explore novel strategies for broader efficacy. Despite these advancements, failures in vaccine research highlight the need to address tumor-associated immune suppression and immune escape mechanisms. In situ vaccination strategies combine innate and adaptive immune stimulation, leveraging tumor-associated antigens to activate dendritic cells and cross-prime CD8+ T cells. Various vaccine modalities, such as nucleotide-based vaccines (e.g., RNA and DNA vaccines), peptide-based vaccines, and cell-based vaccines (including dendritic, T-cell, and B-cell approaches), show significant potential. Plant-based viral approaches, including cowpea mosaic virus and Newcastle disease virus, further expand the toolkit for in situ vaccination. Therapeutic modalities such as chemotherapy, radiation, photodynamic therapy, photothermal therapy, and Checkpoint blockade inhibitors contribute to enhanced antigen presentation and immune activation. Adjuvants like CpG-ODN and PRR agonists further enhance immune modulation and vaccine efficacy. The advantages of in situ vaccination include patient specificity, personalization, minimized antigen immune escape, and reduced logistical costs. However, significant barriers such as tumor heterogeneity, immune evasion, and logistical challenges remain. This review explores strategies for developing potent cancer vaccines, examines ongoing clinical trials, evaluates immune stimulation methods, and discusses prospects for advancing in situ cancer vaccination.

Paclitaxel (PTX) is a widely used anticancer drug for ovarian cancer treatment, but its clinical application is limited by poor water solubility and dose-limiting toxicities. To overcome these challenges, we developed a thermoresponsive, multistep drug delivery system, pNIB/PTX, designed to improve PTX solubility and provide controlled drug release. The pNIB/PTX-3 complex exhibited an initial rapid drug release phase followed by sustained slow release, optimizing both short-term and long-term therapeutic efficacy. At physiological temperatures, the complex demonstrated a precisely controlled drug release mechanism driven by changes in the polymeric micelle structure. In vitro studies showed that pNIB/PTX-3 significantly enhanced therapeutic effects in human ovarian cancer cell lines HeyA8 and SKOV3ip1, compared to PTX alone. In orthotopic ovarian cancer mouse models, a single intraperitoneal injection of pNIB/PTX-3 led to a substantial reduction in tumor size and prolonged survival. This multistep, thermoresponsive delivery system shows strong potential as a promising therapeutic option for dose-dense ovarian cancer treatments, providing improved drug stability, controlled release, and minimized side effects.

Improvements in tumor therapy require a combination of strategies where targeted treatment is critical. We developed a new versatile nanoplatform, MA@E, that generates high levels of reactive oxygen species (ROS) with effective photothermal conversions in the removal of tumors. Enhanced stability liposomes were employed as carriers to facilitate the uniform distribution and stable storage of encapsulated gold nanorods (AuNRs) and Mn-MIL-100 metal-organic frameworks, with efficient delivery of MA@E to the cytoplasm. In the targeted phagocytosis of tumor cells, MA@E can effectively deplete the reduced glutathione (GSH) with increased hydroxyl radicals that combine with Mn²⁺ released from Mn-MIL-100 to trigger Fenton-like reactions, generating ROS that induces cell apoptosis. Exposure to near-infrared (NIR-II) irradiation results in a AuNRs-induced thermogenic effect that expedites the release of Mn²⁺ and promotes Fenton-like reactions, achieving increased production of ^•OH. In the murine tumor model, MA@E effectively removed the implanted tumor tissue within 2 days without any obvious toxic effects. This response is attributed to a synergism involving the photothermal capability of AuNRs and ROS chemodynamic treatment. The proposed MA@E provides a new approach to utilizing unstable nanomaterials in effective tumor therapy.

Diabetes mellitus is a global health threat, with chronic wounds, including oral mucosal wounds, being a severe complication. These wounds are characterized by delayed healing and increased inflammation due to hyperglycemia, affecting patients' quality of life. Current treatments for oral mucosal wounds cannot offer sustained management of these injuries in diabetic patients. Here, a glucose/ROS dual-responsive hydrogel incorporating sitagliptin was developed for the treatment of diabetic oral mucosal wounds. After chemical modification of tetra-armed poly(ethylene glycol) succinimidyl glutarate (tetra-PEG-SG) by dopamine (DA) and tetra-armed poly(ethylene glycol) amine (tetra-PEG-NH₂) by phenylboronic acid (PBA), the resulting hydrogel was capable of rapid gelation, robust tissue adhesion, self-healing, antioxidant capacity, and dual response to glucose and reactive oxygen species (ROS), enabling the feasible injection and stable adherence in the moist oral environment while ensuring sustained therapeutic sitagliptin release. In vivo experiments on oral mucosal defects in diabetic mice revealed that the sitagliptin-loaded hydrogel could effectively reduce inflammation and promote wound healing. Collectively, this finding identifies a potential wound dressing as a therapeutic strategy for diabetic oral mucosal wounds.