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Injuries to the peripheral nervous system are a common clinical issue, causing dysfunctions of the motor and sensory systems. Surgical interventions such as nerve autografting are necessary to repair damaged nerves. Even with autografting, i.e., the gold standard, malfunctioning and mismatches between the injured and donor nerves often lead to unwanted failure. Thus, there is an urgent need for a new intervention in clinical practice to achieve full functional recovery. Nerve guidance conduits (NGCs), providing physicochemical cues to guide neural regeneration, have great potential for the clinical regeneration of peripheral nerves. Typically, NGCs are tubular structures with various configurations to create a microenvironment that induces the oriented and accelerated growth of axons and promotes neuron cell migration and tissue maturation within the injured tissue. Once the native neural environment is better understood, ideal NGCs should maximally recapitulate those key physiological attributes for better neural regeneration. Indeed, NGC design has evolved from solely physical guidance to biochemical stimulation. NGC fabrication requires fundamental considerations of distinct nerve structures, the associated extracellular compositions (extracellular matrices, growth factors, and cytokines), cellular components, and advanced fabrication technologies that can mimic the structure and morphology of native extracellular matrices. Thus, this review mainly summarizes the recent advances in the state-of-the-art NGCs in terms of biomaterial innovations, structural design, and advanced fabrication technologies and provides an in-depth discussion of cellular responses (adhesion, spreading, and alignment) to such biomimetic cues for neural regeneration and repair. 

Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers. 

Porous noble metal nanoparticles have received particular attention recently for their unique optical, thermal, and catalytic functions in biomedicine. However, limited progress has been made to synthesize such porous metallic nanostructures with large mesopores (≥25 nm). Here, a green yet facile synthesis strategy using biocompatible liposomes as templates to mediate the formation of mesoporous metallic nanostructures in a controllable fashion is reported. Various monodispersed nanostructures with well‐defined mesoporous shape and large mesopores (≈ 40 nm) are successfully synthesized from mono‐ (Au, Pd, and Pt), bi‐ (AuPd, AuPt, AuRh, PtRh, and PdPt), and tri‐noble metals (AuPdRh, AuPtRh, and AuPdPt). Along with a successful demonstration of its effectiveness in synthesis of various mesoporous nanostructures, the possible mechanism of liposome‐guided formation of such nanostructures via time sectioning of the synthesis process (monitoring time‐resolved growth of mesoporous structures) and computational quantum molecular modeling (analyzing chemical interaction energy between metallic cations and liposomes at the enthalpy level) is also revealed. These mesoporous metallic nanostructures exhibit a strong photothermal effect in the near‐infrared region, effective catalytic activities in hydrogen peroxide decomposition reaction, and high drug loading capacity. Thus, the liposome‐templated method provides an inspiring and robust avenue to synthesize mesoporous noble metal‐based nanostructures for versatile biomedical applications.

 

Cell encapsulation has been studied for various applications ranging from cell transplantation to biological production. However, current encapsulation technologies focus on cell protection rather than cell regulation that is essential to most if not all cell‐based applications. Here we report a method for cell nanoencapsulation and regulation using an ultrathin biomimetic extracellular matrix as a cell nanocapsule to carry nanoparticles (CN²). This method allows high‐capacity nanoparticle retention at the vicinity of cell surfaces. The encapsulated cells maintain high viability and normal metabolism. When gold nanoparticles (AuNPs) are used as a model to decorate the nanocapsule, light irradiation transiently increases the temperature, leading to the activation of the heat shock protein 70 (HSP70) promoter and the regulation of reporter gene expression. As the biomimetic nanocapsule can be decorated with any or multiple NPs, CN²is a promising platform for advancing cell‐based applications.

 

Cell encapsulation has been studied for various applications ranging from cell transplantation to biological production. However, current encapsulation technologies focus on cell protection rather than cell regulation that is essential to most if not all cell‐based applications. Here we report a method for cell nanoencapsulation and regulation using an ultrathin biomimetic extracellular matrix as a cell nanocapsule to carry nanoparticles (CN²). This method allows high‐capacity nanoparticle retention at the vicinity of cell surfaces. The encapsulated cells maintain high viability and normal metabolism. When gold nanoparticles (AuNPs) are used as a model to decorate the nanocapsule, light irradiation transiently increases the temperature, leading to the activation of the heat shock protein 70 (HSP70) promoter and the regulation of reporter gene expression. As the biomimetic nanocapsule can be decorated with any or multiple NPs, CN²is a promising platform for advancing cell‐based applications.

 

Bacterial contamination of an exposed implantable medical device by the atmosphere of an operating room (OR) is increasingly implicated as a cause of device‐associated infection. Here, OR contamination is modeled in vitro using an aerosolizing system to spray small quantities of staphylococci onto titanium rods. Contaminated rods always manifest culturable bacteria. Self‐assembly is used to create a self‐defensive Ti surface that substantially enhances the rod's resistance to such contamination. Poly(acrylic acid) microgels are electrostatically deposited onto small Ti rods and subsequently loaded by complexation with a cationic antimicrobial peptoid (TM1). The microgels are visualized in situ by optical microscopy, and changes in microgel diameter indicate the loading state. These measurements show that TM1 can be quickly loaded from low‐ionic‐strength buffer and subsequently remained sequestered within the microgels for up to 4 weeks when soaked in phosphate buffered saline. TM1‐loaded microgel‐modified Ti surfaces are contaminated with aerosolized staphylococci, and subsequent assays indicate few or no culturable bacteria. In the absence of nutrients to enable metabolism, this finding suggests that bacteria trigger local TM1 release by contact transfer. The modified surfaces exhibit good in vitro cytocompatibility as manifested by the adhesion, spreading, and metabolic activity of human fetal osteoblasts.

 

Tuning cell shape by altering the biophysical properties of biomaterial substrates on which cells operate would provide a potential shape-driven pathway to control cell phenotype. However, there is an unexplored dimensional scale window of three-dimensional (3D) substrates with precisely tunable porous microarchitectures and geometrical feature sizes at the cell’s operating length scales (10–100 μm). This paper demonstrates the fabrication of such high-fidelity fibrous substrates using a melt electrowriting (MEW) technique. This advanced manufacturing approach is biologically qualified with a metrology framework that models and classifies cell confinement states under various substrate dimensionalities and architectures. Using fibroblasts as a model cell system, the mechanosensing response of adherent cells is investigated as a function of variable substrate dimensionality (2D vs. 3D) and porous microarchitecture (randomly oriented, “non-woven” vs. precision-stacked, “woven”). Single-cell confinement states are modeled using confocal fluorescence microscopy in conjunction with an automated single-cell bioimage data analysis workflow that extracts quantitative metrics of the whole cell and sub-cellular focal adhesion protein features measured. The extracted multidimensional dataset is employed to train a machine learning algorithm to classify cell shape phenotypes. The results show that cells assume distinct confinement states that are enforced by the prescribed substrate dimensionalities and porous microarchitectures with the woven MEW substrates promoting the highest cell shape homogeneity compared to non-woven fibrous substrates. The technology platform established here constitutes a significant step towards the development of integrated additive manufacturing—metrology platforms for a wide range of applications including fundamental mechanobiology studies and 3D bioprinting of tissue constructs to yield specific biological designs qualified at the single-cell level.

 

Scaffold‐guided formation of neuronal‐like networks, especially under electrical stimulation, can be an appealing avenue toward functional restoration of injured nervous systems. Here, 3D conductive scaffolds are fabricated based on printed microfiber constructs using near‐field electrostatic printing (NFEP) and graphene oxide (GO) coating. Various microfiber patterns are obtained from poly(l‐lactic acid‐co‐caprolactone) (PLCL) using NFEP and complexity is achieved via modulating the fiber overlay angles (45°, 60°, 75°, 90°), fiber diameters (15 to 148 µm), and fiber spatial organization (spider web and tubular structure). Upon coating GO onto PLCL microfibers via a layer‐by‐layer (L‐b‐L) assembly technique and in situ reduction into reduced GO (rGO), the obtained conductive scaffolds, with 25–50 layers of rGO, demonstrate superior conductivity (≈0.95 S cm⁻¹) and capability of inducing neuronal‐like network formation along the conductive microfibers under electrical stimulation (100–150 mV cm⁻¹). Both electric field (0–150 mV cm⁻¹) and microfiber diameter (17–150 µm) affect neurite outgrowth (PC‐12 cells and primary mouse hippocampal neurons) and the formation of orientated neuronal‐like networks. With further demonstration of such guidance to neuronal cells, these conductive scaffolds may see versatile applications in nerve regeneration and neural engineering.