ACS Biomaterials Science & Engineering最新文献

The P53 gene is commonly mutated in breast cancer, protein based the gene as anticancer drugs could provide efficient and stable advantages by restoring the function of the wild-type P53 protein. In this study, we describe the creation and utilization of a micelle composed by natural phycocyanin and paclitaxel and grafting anti-HER2 (PPH), which effectively packages and transports recombinant P53 protein with anti-ER (PE), resulting in a new entity designated as PE@PPH, to address localization obstacles and modify cellular tropism to the cell membrane or nucleus. The results indicate that PE@PPH has strong antitumor properties, even at low doses of PTX both in vitro and in vivo. These findings suggest that PE@PPH could be an enhancing micelle for delivering therapeutic proteins and promoting protein functional recovery, particularly in addressing the challenges posed by tumor heterogeneity in breast cancer.

Mimicking the curved collagenous fibers in the cardiac extracellular matrix to fabricate elastic scaffolds in vitro is important for cardiac tissue engineering. Here, we developed sinusoidal polycaprolactone (PCL) fibrous scaffolds with commendable flexibility and elasticity to enhance the contractility of primary cardiomyocytes by employing melt-based electrohydrodynamic (EHD) printing. Microscale sinusoidal PCL fibers with an average diameter of ∼10 μm were printed to mimic the collagenous fibers in the cardiac ECM. The sinusoidal PCL fibrous scaffolds were EHD-printed in a layer-by-layer manner and exhibited outstanding flexibility and elasticity compared with the straight ones. The sinusoidal PCL scaffolds provided an elastic microenvironment for the attaching and spreading of primary cardiomyocytes, which facilitated their synchronous contractive activities. Primary cardiomyocytes also showed improved gene expression and maturation on the sinusoidal PCL scaffolds under electrical stimulation for 5 days. It is envisioned that the proposed flexible fibrous scaffold with biomimetic architecture may serve as a suitable patch for tissue regeneration and repair of damaged hearts after myocardial infarction.

Microvascular engineering seeks to exploit known cell-cell and cell-matrix interactions in the context of vasculogenesis to restore homeostasis or disease development of reliable capillary models in vitro. However, current systems generally focus on recapitulating microvessels embedded in thick gels of extracellular matrix, overlooking the significance of discontinuous capillaries, which play a vital role in tissue-blood exchanges particularly in organs like the liver. In this work, we introduce a novel method to stimulate the spontaneous organization of endothelial cells into nonembedded microvessels. By creating an anisotropic micropattern at the edge of a development-like matrix dome using Marangoni flow, we achieved a long, nonrandom orientation of endothelial cells, laying a premise for stable lumenized microvessels. Our findings revealed a distinctive morphogenetic process leading to mature lumenized capillaries, demonstrated with both murine and human immortalized liver sinusoidal endothelial cell lines (LSECs). The progression of cell migration, proliferation, and polarization was clearly guided by the pattern, initiating the formation of a multicellular cord that caused a deformation spanning extensive regions and generated a wave-like folding of the gel, hinged at a laminin-depleted zone, enveloping the cord with gel proteins. This event marked the onset of lumenogenesis, regulated by the gradual apico-basal polarization of the wrapped cells, leading to the maturation of vessel tight junctions, matrix remodeling, and ultimately the formation of a lumen─recapitulating the development of vessels in vivo. Furthermore, we demonstrate that the process strongly relies on the initial gel edge topography, while the geometry of the vessels can be tuned from a curved to a straight structure. We believe that our facile engineering method, guiding an autonomous self-organization of vessels without the need for supporting cells or complex prefabricated scaffolds, holds promise for future integration into microphysiological systems featuring discontinuous, fenestrated capillaries.

As materials engineered to interact with biological systems for medical purposes, polymeric biomedical materials have revolutionized and are indispensable in modern healthcare. However, aging populations and improving healthcare standards worldwide have resulted in ever-increasing demands for such biomaterials. Currently, many clinically used polymers are derived from nonrenewable petroleum resources, thus spurring the need for exploring alternatives for the next generation of sustainable biomaterials. Other than biomass, this Perspective also spotlights carbon dioxide and postuse plastics as viable resources potentially suitable for biomaterial production. For each alternative feedstock, key recent developments and practical considerations are discussed, including emerging biomaterial applications, possible feedstock sources, and hindrances toward translation and practical adoption. Other than replacements for petroleum-derived polymers, we explore how utilization of these alternatives capitalizes on their intrinsic physiochemical and material properties to achieve their desired therapeutic effects. We hope that this Perspective can stimulate further development in sustainable biomaterials to achieve practical therapeutic benefits as part of a circular materials economy with minimal environmental impact.

During the host response toward implanted biomaterials, macrophages can shift phenotypes rapidly upon changes in their microenvironment within the host tissue. Exploration of this phenomenon can benefit significantly from the development of adequate tools. Creating cell microenvironment alterations on classical hydrogel substrates presents challenges, particularly when integrating them with cell cultivation and monitoring processes. However, having the capability to dynamically manipulate the cell microenvironment on biomaterial surfaces holds significant potential. We introduce magnetically actuated hydrogels (_MadSurface) tailored to induce reversible stiffness changes on polyacrylamide hydrogel substrates with embedded magnetic microparticles in a time-controllable manner. Our investigation focused on exploring the potential of magnetic fields and _MadSurfaces in dynamically modulating macrophage behavior in a programmable manner. We achieved a consistent modulation by subjecting the _MadSurface to a pulsed magnetic field with a frequency of 0.1 Hz and a magnetic field flux density of 50 mT and analyzed exposed cells using flow cytometry and ELISA. At the single-cell level, we identified a subpopulation for which the dynamic stiffness conditions in conjunction with the pulsed magnetic field increased the expression of CD206 in M1-activated THP-1 cells, indicating a consistent shift toward the M2 anti-inflammatory phenotype on _MadSurface. At the population level, this effect was mostly hindered in the culture period utilized in this work. The _MadSurface approach advances our understanding of the interplay between magnetic field, cell microenvironment alterations, and macrophage behavior.

In recent years, silk fibroin (SF) has been incorporated with low crystallinity nanohydroxyapatite (nHA) as a scaffold for various tissue regeneration applications due to the mechanical strength of SF and osteoconductive properties of nHA. However, currently, there is a lack of understanding of the immune response toward the degradation products of SF with nHA composite after implantation. It is known that particulate fragments from the degradation of a biomaterial can trigger an immune response. As the scaffold is made of degradable materials, the degradation products may contribute to the inflammation. Therefore, in this study, the effects of the enzymatic degradation of the SF/nHA scaffold on macrophage response were investigated in comparison to the control SF scaffold. Since the degradation products of a scaffold can influence macrophage polarization, it can be hypothesized that as the SF and SF/nHA scaffolds were degraded in vitro using protease XIV solution, the degradation products can contribute to the polarization of THP-1-derived macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotype. The results demonstrated that the initial (day 1) degradation products of the SF/nHA scaffold elicited a pro-inflammatory response, while the latter (day 24) degradation products of the SF/nHA scaffold elicited an anti-inflammatory response. Moreover, the degradation products from the SF scaffold elicited a higher anti-inflammatory response due to the faster degradation of the SF scaffold and a higher amino acid concentration in the degradation solution. Hence, this paper can help elucidate the contributory effects of the degradation products of SF and SF/nHA scaffolds on macrophage response and provide greater insights into designing silk-based biomaterials with tunable degradation rates that can modulate macrophage response for future tissue regeneration applications.

The demand for small-diameter vascular grafts has been globally increased but still lacks optimal solutions in this category. This study evaluated the feasibility of utilizing human pretreated fresh and nondecellularized umbilical cord arteries (hUCAs) as vascular grafts without needing any immunosuppression process. A mixed lymphocyte reaction assay revealed that hUCAs did not induce lymphocyte proliferation or cytokine production. To assess the in vivo inflammatory response, hUCAs were buried in fatty tissue under the skin of the abdominal wall in the left and right iliac fossas of rats. The average sizes of the implanted hUCAs remained consistent at 30 days post implantation. To evaluate xenogeneic transplantation, hUCAs were grafted to the abdominal aorta below the kidney of Wister rats. Remarkably, all rats exhibited positive revascularization and perfusion, maintaining blood pressure values of around 110/70 mmHg. Doppler ultrasound consistently indicated good circulation, with the three separate echogenic layers corresponding to the three arterial wall layers throughout the assessment period. Grafted rats exhibited normal motor behavior, accompanied by positive responses to thermal and pain stimulation. Blood biochemical values and whole blood cell counts showed no significant differences between pre and post-transplantation. Histological analysis of the grafts revealed no calcification or thrombosis, and a mild chronic inflammatory response was presented. In conclusion, hUCAs maintained their structural and functional properties after transplantation in rats without immunosuppression. This highlights their potential as a source for allogeneic, readily accessible, small-diameter vascular grafts.

Hydroxyapatite nanoparticles (nHA) have gained attention as potential intracellular drug delivery vehicles due to their high binding affinity for various biomolecules and pH-dependent solubility. Yet, the dependence of nHA cytocompatibility on their physicochemical properties remains unclear since numerous studies have revealed starkly contrasting results. These discrepancies may be attributed to differences in size, shape, crystallinity, and aggregation state of nHA, which complicates fundamental understanding of the factors driving nHA cytotoxicity. Here, we hypothesize that nHA cytotoxicity is primarily driven by intracellular calcium levels following the internalization of nHA nanoparticles. By investigating the cytotoxicity of spherical nHA with different crystallinity and dispersity, we find that both lower crystallinity and increased agglomeration of nHA raise cytotoxicity, with nanoparticle agglomeration being the more dominant factor. We show that the internalization of nHA enhances intracellular calcium levels and increases the production of reactive oxygen species (ROS). However, only subtle changes in intracellular calcium are observed, and their physiological relevance remains to be confirmed. In conclusion, we show that nHA agglomeration enhances ROS production and the associated cytotoxicity. These findings provide important guidelines for the future design of nHA-containing formulations for biomedical applications, implying that nHA crystallinity and especially agglomeration should be carefully controlled to optimize biocompatibility and therapeutic efficacy.

Dicalcium phosphate anhydrous (DCPA) presents good biomineralization ability, the strontium element is known for superior bone affinity, and a whisker possesses good mechanical strength; all these are beneficial for improving the drawbacks of hydroxyapatite (HAP) like weaker mechanical properties, poor biomineralization, and slower degradation/absorption. Therefore, a homogeneous precipitation was adopted to synthesize Sr-substituted and DCPA and HAP coexisting whiskers. The composition, structure, and morphology based on urea dosage and substitution content were characterized, and the roles of DCPA, Sr, and whisker shape were investigated. It turned out that Sr-DCPA/HAP biphasic products contained about 19% DCPA and 81% HAP, and both phases occupied the outer and inner parts of the whisker, respectively. Increasing the urea dosage made the morphology transform from a sea urchin shape to fiber clusters and then whiskers, while Sr substitution brought the whisker back to the porous microsphere shape. Only 5% of Sr content and 15 g of urea could maintain the whisker shape. Sr could promote the proliferation of MC3T3-E1 cells even at a higher extract concentration of 10 mg/mL. The cells stayed in a healthy state whether cocultured with the whisker or the microsphere. The unstable DCPA combined with the decreased crystallinity brought by Sr doping contributed to shortening the apatite deposition period to within 7 days. The whisker morphology enhanced the compressive strength of acrylic resin, and the apatite layer helped to reduce the strength loss during soaking. The Sr-DCPA/HAP biphasic whisker with enhanced overall properties possessed more promising potential for biomedical application.