Bioengineering & Translational Medicine最新文献

We developed an injectable hyaluronic acid–metformin (HA–Met) conjugate gel for localized intra-articular delivery to mitigate post-traumatic osteoarthritis (PTOA). Conjugation was verified by Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. In vitro studies showed an initial 24-h burst attributable to unbound Met, followed by prolonged local retention from the conjugated fraction under physiological incubation without hyaluronidase treatment; by contrast, a simple HA + Met mixture released Met in phosphate-buffered saline (PBS) completely in 3 days. In high dosage hyaluronidase-containing PBS, Met retained in the HA–Met conjugate gel up to 4 days. In vivo, Met remained detectable in mouse knee tissues for up to 7 days after a single intra-articular injection of HA–Met conjugate and accumulated with weekly dosing; in contrast, after Met solution or HA + Met mixture injection around 99% of Met was removed from the knee joint in 1 day, low dosage traces of Met remained in the joint up to 2–3 days. In a destabilization of medial meniscus-induced murine PTOA model, weekly HA–Met conjugate injections attenuated cartilage degeneration and joint pathology versus HA or Met alone, which produced only modest effects; sham joints exhibited no pathological changes. The weekly interval was selected to ensure continuous exposure in mice with rapid metabolism and joint clearance and should be viewed as an accelerated proof-of-concept schedule rather than a clinical regimen. These findings support HA–Met conjugate gel as a translational platform that achieves prolonged intra-articular Met retention and disease-modifying benefit in a small-animal PTOA model.

Oocyte activation deficiency is a primary cause of fertilization failure following intracytoplasmic sperm injection, a problem that can potentially be overcome through artificial oocyte activation (AOA). However, concerns persist regarding the safety and efficacy of AOA in clinical practice. We demonstrated that single-pulse nanosecond pulsed electric field (nsPEF) stimulation induced Ca²⁺ signaling patterns that depend on intensity in both mouse and human oocytes, facilitating parthenogenetic activation and blastocyst formation. The sperm-initiated physiological Ca²⁺ oscillations were effectively replicated by a series of Ca²⁺ signals triggered by repeated nsPEF at low or medium intensities, resulting in a significantly higher developmental potential for activated oocytes compared to those treated with A23187 (78.13% vs. 26.70%). The nsPEF stimulation achieved precise manipulation of calcium signaling through two distinct mechanisms: low-intensity nsPEF pulses mediated repetitive extracellular Ca²⁺ influx in an electro-permeable manner, while medium-intensity nsPEF stimulation triggered periodic Ca²⁺ release from the endoplasmic reticulum via the PIP₂–IP₃–IP₃R pathway, generating intracellular Ca²⁺ oscillations that resemble physiological patterns. The non-invasive nsPEF procedure ensured the safety of oocyte activation by maintaining cellular integrity and minimizing stress responses. The efficacy of nsPEF exposure in precisely manipulating Ca²⁺ signaling patterns is also demonstrated in human mature oocytes. This study establishes a quantitative, non-invasive nsPEF protocol for AOA that mimics the activation signaling delivered by sperm. This innovative approach overcomes the limitations of conventional chemical activators by enhancing biosafety and clinical efficacy, particularly for patients experiencing total fertilization failure due to severe male infertility. Its ability to accurately regulate Ca²⁺ signaling presents significant potential for advancing research in various fields, including embryonic development and germ cell differentiation.

Mitral valve repair (MVr) is the preferred surgical treatment for primary mitral regurgitation; however, its success is limited by the lack of validated, accurate, and objective parameters for assessing the complete restoration of physiological mitral valve (MV) mechanics. Consequently, to address this challenge, intraoperative assessment of mitral valve coaptation pressure (MCP) has emerged as a promising approach. This study presents the first precise transcatheter measurement of MCP in animal hearts. Data were obtained using two custom-made force sensors: a 3Fr piezoresistive pressure catheter and a 15Fr flexible piezoelectric sensor. Experiments were conducted in both ex vivo (excised pig hearts activated by a pump) and in vivo (transseptal approach in a living pig) models. In a living pig with a healthy MV under normal hemodynamic conditions (peak systolic left ventricular pressure of 100 mmHg), the MCP ranged from 200 to 300 mmHg (25–40 kPa). Ex vivo experiments demonstrated that MCP was affected by transmitral pressure, mitral function changes (i.e., regurgitation), and MV morphology. These findings provide valuable insights into MV biomechanics and establish a solid foundation for developing medical devices to guide MVr procedures.

Extracellular vesicles (EVs) have emerged as promising therapeutic candidates for a range of neonatal diseases, including sepsis, necrotizing enterocolitis, hypoxic–ischemic encephalopathy (HIE), and bronchopulmonary dysplasia (BPD). Derived from diverse sources such as mesenchymal stem cells, breast milk, and even non-animal systems, EVs exhibit potent anti-inflammatory, immunomodulatory, and tissue-regenerative properties. Preclinical studies in neonatal models demonstrate their ability to reduce inflammation, preserve epithelial and endothelial barrier integrity, modulate immune cell phenotypes, and mitigate organ damage. Despite these encouraging findings, several critical barriers hinder their clinical translation. Challenges include incomplete characterization of EV molecular cargo, variability in isolation and quantification methods, lack of standardized dosing protocols, and limited safety data, particularly regarding procoagulant activity and thrombotic risk. The development of standardized, reproducible isolation techniques, rigorous molecular profiling, and GLP-compliant safety assessments is essential to establish clinical readiness. Current early-phase clinical trials targeting neonatal BPD, prevention of prematurity-related brain injury, and HIE indicate growing translational momentum. If these challenges are addressed, EV-based therapeutics could transform neonatal care, reducing mortality and long-term disability in vulnerable preterm and term infants.

Acute kidney injury (AKI) is a serious condition with significant global impact. To explore mechanisms and biomarkers of heat-stress-induced AKI, we used human kidney organoids derived from induced pluripotent stem cells via suspension culture. Organoids were exposed to 37, 39, and 41°C. At 41°C, we found the viability decreased over time, with cytoskeleton damage, impaired tubule absorption, apoptosis, and collagen deposition. Under extreme heat (41°C), elevated AKI markers KIM-1 and NGAL, along with cell cycle arrest markers TIMP-2*IGFBP7 were detected. Notably, TIMP-2*IGFBP7 appeared at 12 h post-exposure, preceding NGAL and KIM-1. Nascent and steady-state RNA analyses revealed suppressed oxidative phosphorylation and ATP metabolism, along with elevated histone expression, implicating their roles in heat-induced AKI. The data support that kidney organoids serve as a valuable model for investigating heat-induced AKI, providing insights into early injury biomarkers that are valuable for the development of treatments.