Bioengineering & Translational Medicine最新文献

Organophosphate (OP) toxicants remain an active threat to public health and to warfighters in the military. Current countermeasures require near immediate administration following OP exposure and are reported to have controversial efficacies. Acetylcholinesterase (AChE) fused to the human immunoglobulin 1 (IgG1) Fc domain (AChE-Fc) is a potential bioscavenger for OP toxicants, but a reproducible AChE-Fc biomanufacturing strategy remains elusive. This report is the first to establish a comprehensive laboratory-scale bioprocessing strategy that can reproducibly produce AChE-Fc and AChE(W86A)-Fc which is a mutated AChE protein with reduced enzymatic activity. Characterization studies revealed that AChE-Fc and AChE(W86A)-Fc are N-glycosylated dimeric fusion glycoproteins but only AChE-Fc had the capability to bind to paraoxon (a model OP). This AChE-Fc fusion glycoprotein bioprocessing strategy can be leveraged during industrial biomanufacturing development, while the research-grade AChE-Fc proteins can be used to determine the potential clinical relevance of the countermeasure against OP toxicants.

Hydrogels are distinguished by their exceptional ability to absorb and retain large volumes of water within their complex three-dimensional polymer networks, which is advantageous for the development of intraocular lenses (IOLs). Their innate hydrophilicity offers an optimal substrate for the fabrication of IOLs that simulate the natural lens' accommodation, thereby reducing irritation and facilitating healing after surgery. The swelling and water retention characteristics of hydrogels contribute to their notable biocompatibility and versatile mechanical properties. However, the clinical application of hydrogels faces challenges, including managing potential adverse postimplantation effects. Rigorous research is essential to ascertain the safety and effectiveness of hydrogels. This review systematically examines the prospects and constraints of hydrogels as innovative materials for IOLs. Our comprehensive analysis examines their inherent properties, various classification strategies, cross-linking processes, and sensitivity to external stimuli. Additionally, we thoroughly evaluate their interactions with ocular tissues, underscoring the potential for hydrogels to be refined into seamless and biologically integrated visual aids. We also discuss the anticipated technological progress and clinical uses of hydrogels in IOL manufacturing. With ongoing technological advancements, the promise of hydrogels is poised to evolve from concept to clinical reality, marking a significant leap forward in ophthalmology characterized by improved patient comfort, enhanced functionality, and reliable safety.

Restoration of extensive tracheal damage remains a significant challenge in respiratory medicine, particularly in instances stemming from conditions like infection, congenital anomalies, or stenosis. The trachea, an essential element of the lower respiratory tract, constitutes a fibrocartilaginous tube spanning approximately 10–12 cm in length. It is characterized by 18 ± 2 tracheal cartilages distributed anterolaterally with the dynamic trachealis muscle located posteriorly. While tracheotomy is a common approach for patients with short-length defects, situations requiring replacement arise when the extent of lesion exceeds 1/2 of the length in adults (or 1/3 in children). Tissue engineering (TE) holds promise in developing biocompatible airway grafts for addressing challenges in tracheal regeneration. Despite the potential, the extensive clinical application of tissue-engineered tracheal substitutes encounters obstacles, including insufficient revascularization, inadequate re-epithelialization, suboptimal mechanical properties, and insufficient durability. These limitations have led to limited success in implementing tissue-engineered tracheal implants in clinical settings. This review provides a comprehensive exploration of historical attempts and lessons learned in the field of tracheal TE, contextualizing the clinical prerequisites and vital criteria for effective tracheal grafts. The manufacturing approaches employed in TE, along with the clinical application of both tissue-engineered and non-tissue-engineered approaches for tracheal reconstruction, are discussed in detail. By offering a holistic view on TE substitutes and their implications for the clinical management of long-segment tracheal lesions, this review aims to contribute to the understanding and advancement of strategies in this critical area of respiratory medicine.

Chemotherapy treatment outcomes are severely restricted by multidrug resistance (MDR), in which tumors develop a multiple cross-resistance toward drug involving the pump and nonpump resistance mechanisms, resulting in drug efflux and defending against drug toxicity. Herein, we constructed a pH and near infrared (NIR) light responsive nanomedicine DOX@FG based on gold nanorods (GNRs) that demonstrated the potential to improve chemotherapy outcomes by overcoming MDR. DOX@FG was constructed by conjugating folic acid (FA) and doxorubicin (DOX) derivatives onto GNRs, where the DOX derivatives possessed an acid-labile hydrazone bond. Stimulated by the acidic media in endocytic organelles, DOX@FG exhibited a responsive dissociation for the controlled release of chemotherapeutic DOX. Surprisingly, we found the mild photothermal effect elicited by GNRs under NIR irradiation simultaneously inhibited the pump and nonpump resistance mechanisms, enhancing the intracellular DOX accumulation and sensitizing the cancer cells to DOX, collectively amplify the chemotherapy efficacy and delay the MCF-7/ADR breast tumor growth. This intelligent DOX@FG nanomedicine with the potential for two-pronged reversal of MDR may provide a prospective way to encourage chemotherapy efficacy.

Cancer presents a formidable challenge in modern medicine due to the intratumoral heterogeneity and the dynamic microenvironmental niche. Natural or genetically engineered oncolytic bacteria have always been hailed by scientists for their intrinsic tumor-targeting and oncolytic capacities. However, the immunogenicity and low toxicity inevitably constrain their application in clinical practice. When nanomaterials, characterized by distinctive physicochemical properties, are integrated with oncolytic bacteria, they achieve mutually complementary advantages and construct efficient and safe nanobiohybrids. In this review, we initially analyze the merits and drawbacks of conventional tumor therapeutic approaches, followed by a detailed examination of the precise oncolysis mechanisms employed by oncolytic bacteria. Subsequently, we focus on harnessing nanomaterial-assisted oncolytic bacteria (NAOB) to augment the effectiveness of tumor therapy and utilizing them as nanotheranostic agents for imaging-guided tumor treatment. Finally, by summarizing and analyzing the current deficiencies of NAOB, this review provides some innovative directions for developing nanobiohybrids, intending to infuse novel research concepts into the realm of solid tumor therapy.

Conventional dogma suggests that decompression sickness (DCS) is caused by nitrogen bubble nucleation in the blood vessels and/or tissues; however, the abundance of bubbles does not correlate with DCS severity. Since immune cells respond to chemical and environmental cues, we hypothesized that the elevated partial pressures of dissolved gases drive aberrant immune cell phenotypes in the alveolar vasculature. To test this hypothesis, we measured immune responses within human lung-on-a-chip devices established with primary alveolar cells and microvascular cells. Devices were pressurized to 1.0 or 3.5 atm and surrounded by normal alveolar air or oxygen-reduced air. Phenotyping of neutrophils, monocytes, and dendritic cells as well as multiplexed ELISA revealed that immune responses occur within 1 h and that normal alveolar air (i.e., hyperbaric oxygen and nitrogen) confer greater immune activation. This work strongly suggests innate immune cell reactions initiated at elevated partial pressures contribute to the etiology of DCS.

Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA-approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature-sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti-CD47 monoclonal antibodies, when incorporated into subsurface-injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high-grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site-specific modification with hydrolysable “azidoester” adapters, allowing for user-defined release profiles from the hydrogel. Hydrogel-generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8⁺ T-cells and the attenuation of tumor growth in a “cold” syngeneic melanoma model. This study highlights a highly customizable, hydrogel-based delivery system for local protein therapeutic administration to meet diverse clinical needs.

The tumor immune microenvironment has manifested a crucial correlation with tumor occurrence, development, recurrence, and metastasis. To explore the mechanisms intrinsic to osteosarcoma (OS) initiation and progression, this study synthesizes multiple single-cell RNA sequencing data sets, constructing a comprehensive landscape of the OS microenvironment. Integrating single-cell RNA sequencing with bulk RNA sequencing data has enabled the identification of a significant correlation between heightened expression of the fatty acid metabolism-associated gene (C1QBP) and patient survival in OS. C1QBP not only amplifies the proliferation, migration, invasion, and anti-apoptotic properties of OS but also instigates cisplatin resistance. Subsequent investigations suggest that C1QBP potentially promotes macrophage polarization from monocytes/macrophages toward M2 and M3 phenotypes. Consequently, C1QBP may emerge as a novel target for modulating OS progression and resistance therapy.

Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are neurodegenerative disorders caused by the accumulation of misfolded alpha-synuclein protein. Developing effective vaccines against synucleinopathies is challenging due to the difficulty of stimulating an immune-specific response against alpha-synuclein without causing harmful autoimmune reactions, selectively targeting only pathological forms of alpha-synuclein. Previous attempts using linear peptides and epitopes without control of the antigen structure failed in clinical trials. The immune system was unable to distinguish between native alpha-synuclein and its amyloid form. The prion domain of the fungal HET-s protein was selected as a scaffold to introduce select epitopes from the surface of alpha-synuclein fibrils. Four vaccine candidates were generated by introducing specific amino acid substitutions onto the surface of the scaffold protein. The approach successfully mimicked the stacking of the parallel in-register beta-sheet structure seen in alpha-synuclein fibrils. All vaccine candidates induced substantial levels of IgG antibodies that recognized pathological alpha-synuclein fibrils derived from a synucleinopathy mouse model. Furthermore, the antisera recognized pathological alpha-synuclein aggregates in brain lysates from patients who died from DLB, MSA, or PD, but did not recognize linear alpha-synuclein peptides. Our approach, based on the rational design of vaccines using the structure of alpha-synuclein amyloid fibrils and strict control over the exposed antigen structure used for immunization, as well as the ability to mimic aggregated alpha-synuclein, provides a promising avenue toward developing effective vaccines against alpha-synuclein fibrils.