ACS Biomaterials Science & Engineering最新文献

Generation of in vitro tissue models with serially perfused hierarchical vasculature would allow greater control of fluid perfusion throughout the network and enable direct mechanistic investigation of vasculogenesis, angiogenesis, and vascular remodeling. In this work, we have developed a method to produce a closed, serially perfused, multiscale vessel network fully embedded within an acellular hydrogel, where flow through the capillary bed is required prior to fluid exit. We confirmed that the acellular and cellular gel-gel interface was functionally annealed without preventing or biasing cell migration and endothelial self-assembly. Multiscale connectivity of the vessel network was validated via high-resolution microscopy techniques to confirm anastomosis between self-assembled and patterned vessels. Lastly, using a simple acrylic cassette and fluorescently labeled microspheres, the multiscale network was demonstrated to be perfusable. Directed flow from inlet to outlet mandated flow through the capillary bed. This method for producing closed, multiscale vascular networks was developed with the intention of straightforward fabrication and engineering techniques so as to be a low barrier to entry for researchers who wish to investigate mechanistic questions in vascular biology. This ease of use offers a facile extension of these methods for incorporation into organoid culture, organ-on-a-chip (OOC) models, and bioprinted tissues.

Small-diameter vascular grafts still cannot clinically replace autologous blood vessels due to high restenosis rates caused by long-term inflammatory infiltration. Foreign body reactions to vascular grafts induce macrophages to adopt the pro-inflammatory M1 phenotype, releasing inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). This induces a phenotypic switch in smooth muscle cells, eventually leading to intimal hyperplasia. Herein, we constructed small-diameter artificial vascular grafts capable of modulating immune responses through the controlled release of α-ketoglutaric acid (α-KG). Our findings verify that the delivery of α-KG reprograms the macrophage phenotype from a pro-inflammatory M1 to an anti-inflammatory and pro-repair M2 phenotype by regulating the energy metabolism of the tricarboxylic acid cycle (TAC). More interestingly, the delivery of α-KG positively influences the behavior of vascular cells by enhancing the proliferation of human umbilical vein endothelial cells (HUVECs) and inhibiting the expansion of mouse aortic vascular smooth muscle cells (MOVAS), thereby reducing vascular restenosis. In vivo evaluation in rabbit carotid artery replacement confirms the optimal performance of α-KG-doped vascular grafts in terms of endothelial coverage and long-term patency. Collectively, our work presents a promising approach for creating artificial vascular grafts with inflammatory regulation to ensure rapid endothelialization and sustained patency.

Basic amino acid alternating copolymers exhibit exceptional antimicrobial properties and biosafety, yet their application is restricted by the complexity of the synthesis process and low molecular weight (M_n = 1000). In this study, we synthesized a basic amino acid alternating copolymer (Orn-Val) in only one step by the Ugi four-component condensation (Ugi'4CC), achieving high molecular weight (M_n = 20,000) and narrow polydispersity (PDI ≤ 1.10). Furthermore, we observed that factors such as the feed ratio, reaction solvent, and pH significantly influenced the molecular weight and polydispersity of MPE-Orn-Val-Cbz. Moreover, the structure of potassium isocyanate also significantly affected the molecular weight and polydispersity of the products. And it was also demonstrated that the obtained Orn-Val demonstrated excellent antimicrobial properties and biocompatibility. Therefore, this method effectively addresses the limitations associated with the complex synthesis process and low molecular weight of amino acid alternating copolymers.

Cutaneous wound healing is a complex process involving various cellular and molecular interactions, resulting in the formation of a collagen-rich scar with imperfect function and morphology. Dermal fibroblasts are crucial to successful wound healing, migrating to the wound site where they are activated to provide extracellular matrix remodeling and wound closure. Peripheral nerves have been shown to play an important role in wound healing, with loss or damage to these nerves often leading to impaired healing and the formation of chronic nonhealing wounds. Previous research has suggested that sensory nerves secrete trophic factors that can regulate wound healing, including fibroblast activation; however, the direct cell-cell interaction between nerves and fibroblasts has not been extensively studied. To address this knowledge gap, we developed an in vitro co-culture model using a device called the IFlowPlate. This model supports the long-term viability of multiple cell types while allowing for direct contact between sensory nerve cells and dermal fibroblasts. Using the IFlowPlate, we demonstrate that co-culture of dorsal root ganglia with dermal fibroblasts increases fibroblast proliferation, collagen and α-smooth muscle actin expression, and secretion of pro-wound healing factors, suggesting that nerves can promote wound healing by modulating fibroblast activation. The IFlowPlate offers a user-friendly and high-throughput platform to study the in vitro interactions between nerves and a variety of cell types that can be applied to wound healing and other important biological processes.

Osteochondral tissue damage is a serious concern, with even minor cartilage damage dramatically increasing an individual's risk of osteoarthritis. Therefore, there is a need for an early intervention for osteochondral tissue regeneration. 3D printing is an exciting method for developing novel scaffolds, especially for creating biological scaffolds for osteochondral tissue engineering. However, many 3D printing techniques rely on creating a lattice structure, which often demonstrates poor cell bridging between filaments due to its large pore size, reducing regenerative speed and capacity. To tackle this issue, a novel biphasic scaffold was developed by a combination of 3D printed poly(ethylene glycol)-terephthalate-poly(butylene-terephthalate) (PEGT/PBT) lattice infilled with a porous silk scaffold (derived from Bombyx mori silk fibroin) to make up a bone phase, which continued to a seamless silk top layer, representing a cartilage phase. Compression testing showed scaffolds had Young's modulus, ultimate compressive strength, and fatigue resistance that would allow for their theoretical survival during implantation and joint articulation without stress-shielding mechanosensitive cells. Fluorescent microscopy showed biphasic scaffolds could support the attachment and spreading of human mesenchymal stem cells from bone marrow (hMSC-BM). These promising results highlight the potential utilization of this novel scaffold for osteochondral tissue regeneration as well as highlighting the potential of infilling silk materials within 3D printed scaffolds to further increase their versatility.

The standard clinical management of osteomyelitis involves prolonged antibiotic therapy, which frequently necessitates the excision of infected tissues. However, the efficacy of such treatments is increasingly compromised by the rise of antibiotic-resistant pathogens, underscoring an urgent need for innovative approaches. This study introduces a novel composite material designed to offer dual functionality: robust antimicrobial activity and promotion of bone regeneration. The composite integrates biocompatible hydroxyapatite nanoparticles (HA) with a titanium(IV)-metal-organic framework, MIL-125(Ti)-NH₂, impregnated with gentamicin (GM). The solvothermally synthesized MIL-125-NH₂@HA composite demonstrates high cytocompatibility, as evidenced by assays using osteoblasts (U2-OS) and fibroblasts (L929), alongside an absence of hemolytic activity at concentrations of up to 1000 μg/mL. Importantly, the introduction of GM into the composite significantly amplifies its antibacterial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa. Additionally, nanoindentation assessments reveal enhanced mechanical properties of the MIL-125-NH₂@HA composite, indicating the superior elastic performance relative to unmodified HA. The findings of this research are poised to generate significant interest in the development of metal-organic framework (MOF)-based composites for antimicrobial implant applications, presenting a promising avenue for addressing the challenges posed by antibiotic resistance in bone infections.

Cell membrane-coated nanomaterials are increasingly recognized as effective in cancer treatment due to their unique benefits. This study introduces a novel hybrid membrane coating nanoparticle, termed cancer cell membrane (CCM)-outer membrane vesicle (OMV)@Lip-indocyanine green (ICG), which combines CCMs with bacterial OMV to encapsulate ICG-loaded liposomes. Comprehensive analyses were conducted to assess its physical and chemical properties as well as its functionality. Demonstrating targeted delivery capabilities and good biocompatibility, CCM-OMV@Lip-ICG nanoparticles showed promising photothermal and immunotherapeutic effects in tumor models. By inducing hyperthermia-induced tumor therapy and bolstering antitumor immunity, CCM-OMV@Lip-ICG nanoparticles exhibit a synergistic therapeutic effect, providing a new perspective for the management of cancer.

Atopic dermatitis (AD) is a prevalent skin disorder worldwide. However, many AD medications are unsuitable for long-term use due to low therapeutic efficacy and side effects. Extracellular vesicles (EVs) extracted from Pinctada martensii mucus have demonstrated therapeutic efficacy in AD. It is hypothesized that EVs may exert their activity on mammalian cells through their specific contents. In this study, we analyzed the results of miRNA sequencing of the EVs and investigated the potency of highly expressed miR-100-5p in treating AD. To enhance the therapeutic efficiency of the EVs in AD, we developed oxidized sodium alginate (OSA)-carboxymethyl chitosan (CMCS) self-cross-linked hydrogels as a vehicle to deliver the EVs to BALB/c mice with dermatitis. The miR-100-5p in EVs exhibited a favorable anti-inflammatory function, while the hydrogels provided enhanced skin residency. Additionally, its efficacy in inflammation inhibition and collagen synthesis was demonstrated in in vivo experiments. Mechanistically, miR-100-5p in EVs exerted anti-inflammatory effects by inhibiting the expression of FOXO3, consequently suppressing the activation of the downstream NLRP3 signaling pathway. This study underscores the significance of utilizing OSA-CMCS hydrogels as a vehicle for delivering miR-100-5p in P. martensii mucus-derived EVs for the treatment of AD.

Advancing three-dimensional (3D) tissue constructs is central to creating in vitro models and engineered tissues that recapitulate biology. Materials that are permissive to cellular behaviors, including proliferation, morphogenesis of multicellular structures, and motility, will support the emergence of tissue structures. Granular hydrogels in which there is no interparticle cross-linking exhibit dynamic properties that may be permissive to such cellular behaviors. However, designing granular hydrogels that lack interparticle cross-linking but support cellular self-organization remains underexplored relative to granular systems stabilized by interparticle cross-linking. In this study, we developed a polyethylene glycol-based granular hydrogel system, with average particle diameters under 40 μm. This granular hydrogel exhibited bulk stress-relaxing behaviors and compatibility with custom microdevices to sustain cell cultures without degradation. The system was studied in conjunction with cocultures of endothelial cells and fibroblasts, known for their spontaneous network formation. Cross-linking, porosity, and cell-adhesive ligands (such as RGD) were manipulated to control system properties. Toward supporting cellular activity, increased porosity was found to enhance the formation of cellular networks, whereas RGD reduced network formation in the system studied. This research highlights the potential of un-cross-linked granular systems to support morphogenetic processes, like vasculogenesis and tissue maturation, offering insights into material design for 3D cell culture systems.

Calcium phosphate cement (CPC) is an injectable bone cement with excellent biocompatibility, widely used for filling bone defects of various shapes. However, its slow degradation, insufficient mechanical strength, and poor osteoinductivity limit its further clinical applications. In this study, we developed a novel composite magnesium-based calcium phosphate cement by integrating magnesium microspheres into PLGA fibers obtained through wet spinning and incorporating these fibers into CPC. The inclusion of magnesium-based PLGA fibers enhanced the compressive strength and degradation rate of CPC, with the degradation rate of the magnesium microspheres being controllable to allow for the sustained release of magnesium ions. In vitro experiments showed that magnesium-based CPC enhanced the proliferation and migration of MC3T3-E1 and HUVECs. Additionally, the magnesium-based composite CPC not only enhanced osteogenic differentiation of MC3T3-E1 cells but also promoted angiogenesis in HUVECs. In vivo experiments using a vertebral bone defect model in Bama miniature pigs showed that the magnesium-based composite CPC significantly increased new bone formation. Additionally, compared to the CPC group, this composite exhibited significantly higher levels of osteogenic and angiogenic markers, with no inflammation or necrosis observed in the heart, liver, or kidneys, indicating good biocompatibility. These results suggest that magnesium-based composite CPC, with its superior compressive strength, biodegradability, and ability to promote vascularized bone regeneration, holds promise as a minimally invasive injectable material for bone regeneration.