Bioengineering & Translational Medicine最新文献

Ischemic stroke is a serious cerebrovascular disease with limited effective treatments. While stem cell therapy shows promise, ensuring cell survival and integration into neural networks remains a challenge. Recent research shows tissue engineering can greatly fix these flaws. Notably, we focus on the structure–activity relationship of biomaterials. How cell behavior can be most beneficially regulated by changes in the physical structure of the cell carrier itself is certainly a new perspective for cost saving and effectiveness increasing compared to the delivery of expensive biotrophic factors. However, there is a lack of research on biomaterials applied to ischemic stroke, especially in combination with stem cells. No biomaterial has even been approved for clinical trials in stroke. We provide a systematic summary of biomaterials-driven stem cell therapy for ischemic stroke in terms of pathomechanisms, applications, and clinical translational challenges; we attempt to build a bridge from laboratory research to clinical translation in stroke treatment.

Ureteral carcinoma remains a major clinical challenge and requires effective localized treatment. Here, we report a novel ¹²⁵I seed brachytherapy (ISB) and doxorubicin (DOX) chemotherapy integrated ureteral stent (IUS), which enables simultaneous urinary drainage and chemoradiotherapy. This study was divided into three parts. First, ISB and DOX significantly reduced T24 cell viability and inhibited migration and invasion in an in vivo study (p < 0.01). Second, a T24 xenograft mouse model demonstrated that the (DOX + ISB) group exhibited greater tumor suppression than the DOX (p = 0.08) and ISB (p = 0.02) groups, with decreased Ki-67 and Bcl-2 expression and increased apoptosis (all p < 0.01) in an in vitro study. Third, the IUS was successfully implanted in normal beagle dogs (n = 30) without surgical complications. The ureteral diameter increased with increasing cumulative brachytherapy and sustained DOX release (p < 0.05). Histological analysis revealed progressive tissue damage and fibrosis, with increased expression of α-SMA, Caspase-3, and Collagen-1 in the 0.8 mCi + 20 mg DOX group (p < 0.05), whereas PCNA expression was highest in the Control group (0 mCi + 0 mg DOX). In conclusion, the newly designed IUS is safe and technically feasible in animals; clinical studies will be required to evaluate its use in humans.

Elevated levels of low-density lipoprotein cholesterol (LDL-C) play a critical role in the onset and progression of cardiovascular disease (CVD). Inhibitors or monoclonal antibody drugs targeting pro-protein convertase subtilisin/kexin type 9 (PCSK9) are novel cholesterol-lowering medications that can effectively reduce serum LDL-C levels. However, these drugs are usually expensive and require injections, which can reduce patient compliance and increase the financial burden. In this study, we constructed an engineered probiotic strain containing a prokaryotic expression element and a high-affinity fragment of the human PCSK9 nanobody (PCSK9nb). The engineered bacterium was evaluated in vitro and in vivo for its ability to express and release PCSK9nb, as well as for its biocompatibility and stability. The therapeutic potential of the engineered probiotics was confirmed using mouse models of hyperlipidemia and atherosclerosis. We analyzed differences in mouse gut microbiota using high-throughput sequencing and compared the therapeutic efficacy of the engineered bacteria with that of atorvastatin in a mouse model of hyperlipidemia. The engineered bacteria were found to express and release PCSK9nb in vivo after oral administration, achieving the effect of lowering serum cholesterol levels, alleviating atherosclerosis, and reducing body weight. In vivo, PCSK9nb was found to increase hepatic LDL receptor (LDLR) expression levels, decrease serum LDL-C content, regulate the diversity and community structure of gut microbiota, reduce lipid accumulation in the liver, and decrease systemic inflammation. By comparing their efficacy with that of statins, the engineered probiotics demonstrated similar therapeutic effects. The research results provide a new strategy for the development of orally delivered PCSK9 antibody drugs, reducing healthcare costs and minimizing statin drug tolerance.

A major concern of conventional photodynamic therapy is its non-specific toxicity due to off-site drug accumulation. Micelles tend to localize the drug to the tumor site. However, rapid drug release at high concentrations from the micelles to kill the cancer cells remains a formidable task. In this manuscript, we have introduced the 2-nitrobenzyl (2NB)-moiety as the linker between mPEG and the photosensitizer, chlorin e6 (Ce6), to prepare the conjugate, mPEG(2-nitrobenzyl)Ce6. We envision that 2NB as a linker between hydrophobic, Ce6, and hydrophilic mPEG would be more effective in releasing Ce6 by disassembling PEGylated 2-nitrobenzyl chlorin e6 (mPNCe6) Ms. Characterization through Fourier transform infrared spectroscopy and ¹H, ¹³C nuclear magnetic resonance spectra validated the successful synthesis of the conjugate. By conjugating Ce6 into the hydrophobic core of the micelles, exposure to near-infrared light significantly hastened the dissociation of the micelles, facilitating a controlled and rapid release of Ce6's hydrophobic components within the micelles. A cellular uptake study was performed, showing that Ce6 conjugation has improved the uptake of Ce6. The cell viability assay revealed that the formulation had shown concentration-dependent cytotoxicity upon laser irradiation. mPNCe6 group with laser irradiation has generated abundant reactive oxygen species (ROS) inside cells and exhibited green solid fluorescence, indicating the efficient delivery of Ce6 by mPNCe6 micelles and its excellent ROS generation ability inside cells upon laser irradiation. Further, in vivo studies on MOC2 tumor-bearing mice demonstrate reduced tumor growth, lung metastasis, and drug accumulation in the tumor region. The developed nanomedicine could be a potential treatment strategy for oral cancer, minimizing the occurrence of lung metastasis.

The homeostasis of branched-chain amino acids (BCAAs) plays a crucial role in maintaining health, and the accumulation of BCAAs can lead to various diseases. Therefore, exogenous degradation or conversion of excessive BCAAs may help alleviate diseases caused by BCAA accumulation, such as maple syrup urine disease. This study utilized synthetic biology approaches to engineer two strains for efficient BCAA catabolism successfully—ECN-Deg and ECN-Tra—by integrating specific metabolic pathways into the chassis strain, Escherichia coli Nissle 1917 (ECN). ECN-Deg integrates a metabolic module for BCAA degradation, while ECN-Tra integrates a metabolic module for BCAA transformation. Both engineered strains demonstrate efficient BCAA catabolism in vitro and in vivo. In a high-BCAA mouse model, ECN-Deg and ECN-Tra alleviated liver and ileal damage caused by excessive BCAAs and reduced systemic inflammation levels. Furthermore, ECN-Deg and ECN-Tra were able to modulate the gut microbiota, increasing the richness of Akkermansia muciniphila and Mucispirillum schaedleri, which are associated with health benefits. Additionally, they reduced the richness of the pathogenic bacterium Streptococcus pasteurianus. Thus, this study lays the foundation for the development of probiotics for the treatment of BCAAs metabolic disorders and BCAAs-related chronic diseases.

Atherosclerosis (AS) is a complex cardiovascular disease characterized by endothelial dysfunction, dyslipidemia, and immune-inflammatory responses, leading to arterial plaque formation and potentially fatal complications such as myocardial infarction and stroke. Traditional treatments, such as statins, often pose challenges due to their side effects and limited efficacy. In this study, we explore a novel therapeutic approach utilizing engineered endothelial cells (ECs) targeting probiotic extracellular vesicles loaded with dihydrotanshinone I (DHT) (EC-BEVs^DHT), a bioactive compound derived from Danshen (Salvia miltiorrhiza Bunge). With the characterization of EC-BEVs^DHT by transmission electron microscope and nanoparticle tracking analysis, EC-BEVs^DHT exhibited typical spherical morphology and particle size distribution. High-performance liquid chromatography coupled with tandem mass spectrometric confirmed the expression of the ECs-targeting peptide VSSSTPR in EC-BEVs^DHT and EC-BEVs^DHT. We further investigated the anti-atherosclerotic effects and molecular mechanisms of EC-BEVs^DHT on human umbilical vein endothelial cells (HUVECs) and Apolipoprotein E-deficient (ApoE^−/−) C57BL/6J mice. We found that EC-BEVs^DHT attenuated oxidized low-density lipoprotein induced HUVECs injury in vitro and decreased AS in ApoE^−/− mice in vivo. Our findings suggest that EC-BEVs^DHT hold promise as a safe and effective therapeutic strategy for AS, offering potential advantages over traditional treatments.

Peripheral nerves are vulnerable to trauma, pressure, and surgical injuries, complicating the regeneration process. While the autograft remains the gold standard for recovery, limitations such as tissue availability and donor site morbidities have led to the exploration of the allografts. However, conventional detergent-based decellularization methods in preparing allografts often cause residual toxicity and damage to the extracellular matrix (ECM). To address such challenges, we propose a sodium hydroxide (NaOH)-based decellularization technique that minimizes harmful residues. Our findings demonstrate that this method effectively removes inflammatory materials while preserving the ECM components and structures, and significantly reduces lipid and detergent residues. In vitro studies confirmed that the human nerves processed with the NaOH-based decellularization technique show low cytotoxicity and support elevated cell viability and proliferation. We further compared the performance of NaOH-based decellularized human nerves with that of autografts through an in vivo rabbit sciatic nerve defect model. NaOH-based decellularized nerves showed functional recovery comparable to autografts. Our findings demonstrate structural regeneration through neurofilament and laminin expression, indicating recovery levels similar to those of autografts. This study highlights that decellularized human nerve grafts through the NaOH-based protocol can promote nerve regeneration comparable to autografts, which can offer a safe and effective option for the treatment and reconstruction of peripheral nerve defects.