Bioengineering & Translational Medicine最新文献

Preterm brain injury affects both white and gray matter, including altered cortical development and gyrification, with associated neurodevelopmental sequelae such as cerebral palsy and learning deficits. The preterm brain also displays regionally heterogeneous responses to both injury and treatment, suggesting that drug combinations may be needed to provide global neuroprotection. We developed an extremely preterm-equivalent organotypic whole hemisphere (OWH) slice culture mild injury model using the gyrencephalic ferret brain to probe treatment mechanisms of promising therapeutic agents and their combination. Regional and global responses to injury and treatment were assessed by cell death quantification, machine learning-augmented morphological microglia assessments, and digital transcriptomics. Using two promising therapeutic agents, azithromycin (Az) and erythropoietin (Epo), we show minimal neuroprotection by either therapy alone, but evidence of synergistic neuroprotection by Az*Epo both globally and regionally. This effect of Az*Epo involved augmentation of transcriptomic responses to injury related to neurogenesis and neuroplasticity and downregulation of transcripts involved in cytokine production, inflammation, and cell death. With the increasing need to develop therapies for extremely preterm brain injury, the ferret OWH slice culture model provides a high-throughput platform to examine combinations of therapeutics as part of a preclinical therapeutic pipeline.

Over the past two decades, an increasing body of evidence has underscored the significant role of the mechanical properties of biological tissues in maintaining tissue functions and regulating cellular changes, such as proliferation, migration, and differentiation. Throughout disease progression, such as in cancers, bone defects, and cardiac conditions, the mechanical microenvironment of tissues can undergo dramatic changes, exerting profound effects on disease development. Adipose tissues are inherently mechanosensitive and mechanoresponsive, continually exposed to various mechanical stresses in daily life. The hypertrophy and accumulation of adipocytes can lead to obesity, a condition strongly associated with numerous health risks, like diabetes and cancers. In this review, we aim to elucidate the reciprocal mechanical interaction between adipose tissues and disease progression, encompassing cancers, bone defects, and cardiac pathologies. The existing literature suggests that alterations in the mechanical microenvironment during disease advancement may impede adipogenic differentiation, induce adipocyte dedifferentiation, and escalate the secretion of inflammatory cytokines. Conversely, dysregulation of adipose tissues can result in the deposition of extracellular matrix components, stiffening the microenvironment and fostering disease progression in a cyclical fashion. Therefore, in future treatments of related diseases, a combined approach integrating mechanotherapeutics and obesity management holds promise for achieving the desired enhanced therapeutic outcomes.

Recent developments in synthetic three-dimensional (3D) gel microenvironments for cell culture have enabled the advancement of bioengineered organ-specific cell niches that resemble the native 3D tissue architecture and mechanics. In particular, the application of 3D cell cultures based on miniaturized hydrogel scaffolds for toxicological analyses is attracting increasing interest because of their facile adaptability to on-chip systems and potential as novel in vitro screening tools. We summarize the current progress in microgel-based 3D cells integrated into biochip platforms and their utilization for the in vitro toxicity evaluation of chemicals and drug candidates. We emphasize the development of tissue-mimicking microgel systems combined with automated gel microarray chips and organ-on-a-chip devices. This review begins with the microscale hydrogel scaffolds that encapsulate mammalian cells and are used for in vitro tissue mimicry purposes. Furthermore, an overview of microgel-based tissue modeling approaches to toxicity testing and screening is provided, along with their technical advantages in drug discovery and alternatives to animal testing.

Glioblastoma (GBM) is a highly malignant brain tumor with a poor survival prognosis of 12–15 months despite current therapeutic strategies. Diagnosing GBM is challenging, often requiring invasive techniques such as tissue biopsy and imaging methods that can provide inconclusive results. In this regard, liquid biopsy represents a promising alternative, providing tumor-derived information from less invasive sources such as blood or cerebrospinal fluid. However, the typically low concentrations of these biomarkers pose challenges for traditional detection techniques, limiting their sensitivity and specificity. Recent advances in microfluidics offer a potential solution by enhancing the isolation and detection of tumor-derived cells and molecules, thus improving their detectability. This review discusses the latest progress in microfluidic-based liquid biopsy systems for glioblastoma, laying the basis for future diagnostic practices that are less invasive and more accurate. As these technologies evolve, they hold the potential to transform GBM diagnosis and monitoring, ultimately improving patient outcomes.

Cartilage regeneration presents unique challenges due to its avascular structure, sparse cell population, and limited regenerative capacity. Recent years have seen significant advancements in the field, which warrant an integrated review that connects chondrogenesis and its practical application. This review aims to deliver comprehensive and analytical guidelines for understanding the complex process of chondrogenesis, emphasizing its critical role in cartilage regeneration. It reviews key inducers such as growth factors, mechanical stimuli, hypoxia, and electric fields, as well as their synergistic integration with biomaterials to facilitate effective strategies for repairing and regenerating damaged cartilage tissue. In addition to exploring these advancements, the paper also provides a critical evaluation of current methods used to assess chondrogenesis in in vitro and in vivo models, identifying gaps and possibilities for improvement. A particular focus is placed on addressing the translational challenges that hinder the clinical implementation of cutting-edge research findings, offering actionable strategies to bridge the gap between laboratory discoveries and patient outcomes. By examining emerging trends and consolidating recent innovations, this review aims to offer a holistic perspective on cartilage repair. It serves as a guide for researchers and clinicians, advocating for collaborative, interdisciplinary approaches to advance the field and deliver improved therapeutic solutions for cartilage-related conditions.

Traumatic brain injury (TBI) remains a major global health challenge, characterized by high morbidity and mortality rates. Despite advances in neuroscience, the blood–brain barrier (BBB) limits the effectiveness of potential neuroprotective treatments. Recent nanotechnology breakthroughs have led to smart drug delivery systems that can cross the BBB and target injured brain areas. However, achieving the specificity needed to deliver therapies to affected neurons remains a challenge. In previous work, we developed a mixed-layered dendrimer functionalized with 2-deoxyglucose (2DG-D) for selective neuronal drug delivery. In this study, we explore the therapeutic potential of rosiglitazone (Rosi) for pediatric TBI by creating a 2DG-D-Rosi nanosystem, where Rosi is conjugated to 2DG-D to improve its solubility, bioavailability, and targeted delivery to injured neurons. In vitro, 2DG-D-Rosi demonstrated high neuronal uptake, sustained drug release, and excellent biocompatibility. It significantly reduced neuronal apoptosis, reactive oxygen species formation, pro-inflammatory cytokine expression, and caspase activity, outperforming free Rosi. In vivo, using a pediatric TBI mouse model, 2DG-D-Rosi improved neuronal targeting, reduced neuroinflammation, and enhanced behavioral outcomes. This research highlights 2DG-D-Rosi as a promising nanotherapeutic platform for precise TBI treatment and sets the stage for developing more effective therapies for this challenging condition.

Sensitive and effective detection of epidermal growth factor receptor (EGFR) mutations is crucial for the early screening and diagnosis of non-small cell lung cancer (NSCLC). In this study, we assessed the sensitivity and specificity of the molecular switch technology combined with blocker primers for detecting EGFR exon 19 mutations. We demonstrated that this novel method allows real-time detection of mutated templates on a qPCR platform. Moreover, applying this method to cell-free DNA samples enhances the mutation detection rate.

Placental dysfunction leads to pregnancy-related disorders that affect up to 15% of pregnancies. Several of these, such as preeclampsia, are symptomatically managed but have no curative treatments other than preterm delivery. Placental dysfunction arises from improper placental development, leading to restricted blood vessel formation and a hypoxic placental microenvironment. The development of placental therapeutics is challenging due to the complex physiology that enables the placenta to control uptake and transport. Here, we use a simple culture system that combines hypoxia and trophoblast syncytialization to model the functional syncytiotrophoblast layer of the placenta under hypoxic stress. Using this model, we evaluate the impact of hypoxia on lipid nanoparticle (LNP)-mediated mRNA delivery. Our data show that hypoxia hinders syncytiotrophoblast formation in vitro. Despite this, LNP delivery to syncytiotrophoblasts increases protein translation and secretion, particularly under hypoxic conditions. Further, we show delivery of a therapeutic mRNA, placental growth factor (PlGF), to syncytiotrophoblasts in hypoxia, which restored diminished PlGF levels back to normoxic controls. These findings provide an LNP platform for efficient mRNA delivery to hypoxic trophoblasts and demonstrate the importance of considering hypoxia towards the development of drug delivery platforms for placental therapeutics.

Mesenchymal stromal cell (MSCs)-based therapies have emerged as a promising approach for inflammatory bowel disease (IBD) treatment due to their immunosuppressive and regenerative properties. However, clinical trials have shown limited therapeutic effectiveness, largely because of low efficiency in penetrating the inflamed colon and their inconsistent in vivo immunomodulatory ability. In this study, we generated genetically engineered adipose-derived human MSCs constitutively expressing CXC chemokine receptor 4 and interleukin 10 (CXCR4-IL10-MSCs) to promote their delivery to the inflamed colon and enhance their immunosuppressive capability. Compared to unmodified MSCs, CXCR4-IL10-MSCs exhibited enhanced trafficking to the inflamed colon and achieved improved therapeutic effects in dextran sulfate sodium (DSS)-challenged colitic mice. Upon a chronic DSS re-challenge, CXCR4-IL10-MSCs showed enhanced long-term protective effects. These findings demonstrate that stable ectopic expression of CXCR4 and IL10 enhances the therapeutic efficacy of MSCs and supports the development of an optimized MSC-based product capable of inducing an improved long-term protective immune memory in IBD.

The fibrotic encapsulation of implantable medical devices reduces diffusion-based mass transport and electrical conductivity between the tissue and implant, limiting many devices to weeks-long rather than years-long lifetimes. Most strategies to overcome fibrosis take a passive, materials-driven approach to mitigate the chemical and mechanical mismatch at the tissue-implant interface through superficial or structural implant modifications. Recent advancements in microfabrication and mechanotherapy have led engineers to incorporate smart and active mechanical actuation systems into implantable devices that use pressure, vibration, and integrated electronics to perpetually overcome effects of the foreign body response. Here, we highlight medical applications where active antifibrotic strategies outperform passive strategies in terms of device lifetimes and therapeutic outcomes, outline engineering design considerations for integrating active strategies, and discuss challenges in developing dynamic and living implants.