Bioengineering & Translational Medicine最新文献

Self-organizing brain organoids provide a promising tool for studying human development and disease. Here we created human forebrain organoids with stable and homogeneous expression of channelrhodopsin-2 (ChR2) by generating AAVS1 safe harbor locus-targeted, ChR2 knocked-in human pluripotent stem cells (hPSCs), followed by the differentiation of these genetically engineered hPSCs into forebrain organoids. The resulting ChR2-expressing human forebrain organoids showed homogeneous cellular expression of ChR2 throughout entire regions without any structural and functional perturbations and displayed consistent and robust neural activation upon light stimulation, allowing for the non-virus mediated, spatiotemporal optogenetic control of neural activities. Furthermore, in the hybrid platform in which brain organoids are connected with spinal cord organoids and skeletal muscle spheroids, ChR2 knocked-in forebrain organoids induced strong and consistent muscle contraction upon brain-specific optogenetic stimulation. Our study thus provides a novel, non-virus mediated, preclinical human organoid system for light-inducible, consistent control of neural activities to study neural circuits and dynamics in normal and disease-specific human brains as well as neural connections between brain and other peripheral tissues.

Triple-negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of targetable receptors and sometimes poor response to chemotherapy. The transforming growth factor beta (TGFβ) family of proteins and their receptors (TGFRs) are highly expressed in TNBC and implicated in chemotherapy-induced cancer stemness. Here, we evaluated combination treatments using experimental TGFR inhibitors (TGFβi), SB525334 (SB), and LY2109761 (LY) with paclitaxel (PTX) chemotherapy. These TGFβi target TGFR-I (SB) or both TGFR-I and TGFR-II (LY). Due to the poor water solubility of these drugs, we incorporated each of them in poly(2-oxazoline) (POx) high-capacity polymeric micelles (SB-POx and LY-POx). We assessed their anticancer effect as single agents and in combination with micellar PTX (PTX-POx) using multiple immunocompetent TNBC mouse models that mimic human subtypes (4T1, T11-Apobec and T11-UV). While either TGFβi or PTX showed a differential effect in each model as single agents, the combinations were consistently effective against all three models. Genetic profiling of the tumors revealed differences in the expression levels of genes associated with TGFβ, epithelial to mesenchymal transition (EMT), TLR-4, and Bcl2 signaling, alluding to the susceptibility to specific gene signatures to the treatment. Taken together, our study suggests that TGFβi and PTX combination therapy using high-capacity POx micelle delivery provides a robust antitumor response in multiple TNBC subtype mouse models.

Vaccination is the most effective strategy to combat influenza. Ideally, potent and persistent vaccine effects would be induced with a single vaccine dose. Here, we designed a virus-like particle (VLP)-based vaccine presenting multiple copies of the influenza hemagglutinin (HA) from A/Puerto Rico/8/1934 (PR8HA-VLP) and examined its immunogenicity and protective efficacy in ferrets. Serum-neutralizing antibodies were effectively induced against the homologous virus at 3-week post-vaccination with a single dose of PR8HA-VLP with or without adjuvants. When the single-immunized ferrets were challenged with the homologous virus, virus replication in the nasal mucosa was significantly reduced. Long-term monitoring of serum titers revealed that after adjuvanted vaccination with PR8HA-VLP, neutralizing antibodies were retained at similar levels 20- to 183-week post-vaccination, although a 4- to 8-fold titer decline was observed from 3- to 20-week post-vaccination. Boost immunization at 183 weeks after the first immunization elicited higher neutralizing antibody titers than those at 3 weeks after the initial immunization in most of the animals. These results confirm that nanoparticle-based vaccines are a promising approach to effectively elicit durable multiyear neutralizing antibody responses against influenza viruses.

Inflammatory bowel disease (IBD) is a chronic and unspecific inflammatory disorder of the gastrointestinal tract, and current treatment options often fail to maintain long-term remission. Studies have shown that propionate level is reduced in fecal samples from patients with IBD. Propionate can ameliorate IBD through intestinal epithelial cells and immune regulation, but its effects on the inflammatory microenvironment and macrophage differentiation have not been widely studied. To address this, we constructed an engineered propionate-producing probiotic (EcNP3) to achieve sustained restoration of propionate levels in the gut and increase its bioavailability. DSS-induced experimental intestinal inflammation model was used to evaluate the effect of EcNP3 on improving the intestinal mucosal barrier and increasing the proportion of anti-inflammatory macrophages. It was found that EcNP3 exhibited a restorative effect on the depletion of peritoneal anti-inflammatory macrophages (F4/80hiCD11bhi) and significantly improved the expression level of IL-10. Simultaneously, the expression of IL-1β, IL-6, and CXCL1 was downregulated while inhibiting apoptosis of tissue-resident macrophages ex vivo. Further investigation revealed that EcNP3 regulates IL-10 expression through G protein-coupled receptor 43 and histone deacetylase. Furthermore, EcNP3 significantly inhibited the protein expression of HDAC1 and promoted the histone acetylation level of cells. Finally, EcNP3 significantly improved DSS-induced colitis in mice by increasing mucus production and reducing inflammatory infiltration. Our results suggest that the engineered live biotherapeutic product EcNP3 is a safe and potently efficacious treatment for IBD, which defines a novel strategy in IBD therapy through macrophage IL-10 signaling.

Hydrogels have been used in the clinic since the late 1980s with broad applications in drug delivery, cosmetics, tissue regeneration, among many other areas. The past three decades have witnessed rapid advances in the fields of polymer chemistry, crosslinking approaches, and hydrogel fabrication methods, which have collectively brought many new hydrogel products, either injectable or non-injectable, to clinical studies. In an article published in 2020 entitled “Hydrogels in the clinic”, we reviewed the clinical landscape and translational challenges of injectable hydrogels. Here, we provide an update on the advances in the field and also extend the scope to include non-injectable hydrogels. We highlight recently approved hydrogel products, provide an update on the clinical trials of injectable hydrogels, and discuss active clinical trials of topically applied and implantable hydrogels.

Postoperative critical care management of congenital heart disease patients requires prompt intervention when the patient deviates significantly from clinician-determined vital sign and hemodynamic goals. Current monitoring systems only allow for static thresholds to be set on individual variables, despite the expectations that these signals change as the patient recovers and that variables interact. To address this incongruency, we have employed statistical process monitoring (SPM) techniques originally developed to monitor batch industrial processes to monitor high-frequency vital sign and hemodynamic data to establish multivariate trajectory maps for patients with d-transposition of the great arteries following the arterial switch operation. In addition to providing multivariate trajectory maps, the multivariate control charts produced by the SPM framework allow for assessment of adherence to the desired trajectory at each time point as the data is collected. Control charts based on slow feature analysis were compared with those based on principal component analysis. Alarms generated by the multivariate control charts are discussed in the context of the available clinical documentation.

Long-lasting vaginal dosage forms could improve the therapeutic efficacy of vaginal microbicides, but achieving long-term delivery to the vaginal canal has been a significant challenge. To advance understanding of vaginal dosage retention and biodistribution, we describe a method of noninvasive imaging with ⁸⁹Zr-labeled bioadhesive nanoparticles (BNPs) in non-human primates. We additionally examined the safety of repeated BNP application. BNPs administered vaginally to cynomolgus monkeys were still detected after 24 h (1.7% retention) and 120 h (0.1% retention). BNPs did not translocate to the uterus or into systemic circulation. Analysis of inflammatory biomarkers in the vaginal fluid and plasma suggest that BNPs are safe and biocompatible, even after multiple doses. BNPs are a promising delivery vehicle for vaginally administered therapeutics. Further studies using the non-human primate imaging materials and methods developed here could help advance clinical translation of BNPs and other long-lasting vaginal dosage forms.

Confounding results of engineered mesenchymal stem cells (MSCs) used as cellular vehicles has plagued technologies whereby success or failure of novel approaches may be dismissed or inaccurately ascribed solely to the biotechnology platform rather than suitability of the human donor. Polymeric materials were screened for non-viral engineering of MSCs from multiple human donors to deliver bone morphogenic protein-4 (BMP4), a protein previously investigated in clinical trials for glioblastoma (GBM) to combat a subpopulation of highly invasive and tumorigenic clones. A “smart technology” that target the migratory and stem-like nature of GBM will require: (1) a cellular vehicle (MSC) which can scavenge and target residual cells left behind after surgical debulking and deliver; (2) anti-glioma cargo (BMP4). Multiple MSC donors are safely engineered, though varied in susceptibility to accept BMP4 due to intrinsic characteristics revealed by their molecular signatures. Efficiency is compared via secretion, downstream signaling, differentiation, and anti-proliferative properties across all donors. In a clinically relevant resection and recurrence model of patient-derived human GBM, we demonstrate that nanoengineered MSCs are not “donor agnostic” and efficacy is influenced by the inherent suitability of the MSC to the cargo. Therefore, donor profiles hold greater influence in determining downstream outcomes than the technical capabilities of the engineering technology.

Antibody-drug conjugates (ADCs), chemotherapeutic agents conjugated to an antibody to enhance their targeted delivery to tumors, represent a significant advancement in cancer therapy. ADCs combine the precise targeting capabilities of antibodies and the potent cell-killing effects of chemotherapy, allowing for enhanced cytotoxicity to tumors while minimizing damage to healthy tissues. Here, we provide an overview of the current clinical landscape of ADCs, highlighting 11 U.S. Food and Drug Administration (FDA)-approved products and discussing over 500 active clinical trials investigating newer ADCs. We also discuss some key challenges associated with the clinical translation of ADCs and highlight emerging strategies to overcome these hurdles. Our discussions will provide useful guidelines for the future development of safer and more effective ADCs for a broader range of indications.