Bioengineering & Translational Medicine最新文献

Hyperexcitability of peripheral sensory neurons plays a critical role in the development and maintenance of chronic pain. Pharmacological analgesics used in clinics reduce neuronal activity. They often come with non-negligible side effects. Optogenetic approaches can modulate neuronal activity and are attracting growing interest for therapeutic uses, but the delivery of light in different parts of the body requires the development of specific optoelectronic interfaces. We designed and produced a microfabricated optoelectronic implant to deliver yellow light (559 nm) onto the sciatic nerve. We have surgically implanted the device in transgenic mice expressing the yellow light-sensitive inhibitory archaerhodopsin (ArchT) in nociceptive neurons. Yellow light induced a significant reduction in the responses of the nociceptive neurons and curbed the behavioral responses to noxious mechanical and thermal stimuli. Remarkably, the yellow light-related inhibition did not alter the behavioral responses evoked by innocuous mechanical stimulation or by intense inflammation. The optoelectronic implants showed reliable and reproducible opto-electrical performance. For stimulation parameters used in vivo (3.3 V, 60–80 mW/mm², 20 s train pulses, 1 Hz, 80% duty-cycle, and an inter-train interval of 1 s), limited temperature increase was measured in an environment mimicking neural tissue surrounded by muscle and fat. Similarly, the basal sensitivity of the implanted mice remains comparable to non-implanted mice, suggesting a safe integration of the soft electronic device. Our study confirmed that optoelectronic implants tailored to the sciatic nerve can provide specific light spectra and intensities at adequate levels for the optogenetic actuator to trigger significant electrophysiological and behavioral responses in pain perception.

Pulmonary hypertension (PH) is defined as an elevation in the right ventricular (RV) afterload, characterized by increased hemodynamic pressure in the main pulmonary artery (PA). Elevations in RV afterload increase RV wall stress, resulting in RV remodeling and potentially RV failure. From a biomechanical standpoint, the primary drivers for RV afterload elevations include increases in pulmonary vascular resistance (PVR) in the distal vasculature and decreases in vessel compliance in the proximal arteries. However, the individual contributions of the various vascular remodeling events toward the progression of PA pressure elevations and altered vascular hemodynamics remain elusive. In this study, we used a subject-specific one-dimensional (1D) fluid–structure interaction (FSI) model to investigate the alteration of pulmonary hemodynamics in PH and to quantify the contributions of decreased compliance and increased resistance toward increased main pulmonary artery (MPA) pressure. We used a combination of subject-specific hemodynamic measurements, ex-vivo mechanical testing and histological analysis of arterial tissue specimens, and ex-vivo x-ray micro-tomography imaging to develop the 1D FSI model and dissect the contribution of PA remodeling events toward alterations in the MPA pressure waveform. Both the amplitude and pulsatility of the MPA pressure waveform were analyzed. Our results indicated that increased distal resistance has the greatest effect on the increase in maximum MPA pressure, while decreased vessel compliance caused significant elevations in the characteristic impedance. The method presented in this study will serve as an essential step toward understanding the complex interplay between PA remodeling events that lead to the most adverse effect on RV function.

Bioreactors have become indispensable tools in spine research, enabling long-term intervertebral disc culture under controlled biological and mechanical conditions. Conventional systems are often limited to uniaxial loading, restricting their ability to replicate the complex, multidirectional biomechanics of the spine. To overcome this limitation, we developed a next-generation bioreactor capable of simulating multiaxial motions while preserving the disc's biological environment. In this study, we investigated the effects of complex loading patterns on early disc degeneration by subjecting bovine whole-organ discs to combined extension, lateral bending, and torsion at 0.3 Hz for 2 h daily over 14 days. To assess the impact of loading magnitude and the specific contribution of torsion, discs were exposed to either low- or high-angle rotations, with or without torsional loading at higher angles. Histological analysis revealed a marked loss of glycosaminoglycans (GAG) and collagen type II within the inner annulus fibrosus and transitional nucleus pulposus (NP), encompassing the transition zone (TZ), as well as GAG depletion in the central NP. Matrix degradation was observed across all loading conditions, with the most severe breakdown occurring under high-angle extension, bending, and torsion. All loading regimes induced cell death in the TZ and central NP, although torsion-free loading better maintained cell viability. These findings highlight the TZ, alongside the commonly affected NP, as a critical early site of degeneration. The study further underscores the importance of incorporating multiaxial loading in disc degeneration models and provides new insights into the biomechanical mechanisms underlying disc pathology.

Extranuclear organelle transplantation, an emerging field in cell biology and bioengineering, presents innovative therapeutic possibilities by transferring organelles such as mitochondria between cells or across species. In living organisms, mitochondria and chloroplasts are closely related to converting substances and energy within cells. Transplantation therapy of mitochondria seeks to rebuild cell metabolic function in diseased or damaged cells and has broad application potential in treating metabolic diseases. The therapies provide a distinctive technology for cellular restoration by targeting energy generation at the organelle level, which will offer new energy resources for animal cells. At present, mitochondrial transplantation therapy has been applied as a novel approach to rescue patients in clinical settings, and chloroplast-based transplantation endows animal cells to utilize light energy (photosynthetic animal cells). In this review, we discuss the exciting development and application prospects of mitochondrial and photosynthetic therapy in biomedicine. The technology of extranuclear transplantation would exert innovative and profound impacts on biological therapy.

Chemical ablative therapies offer effective alternatives for tumor treatment, particularly when surgical resection or heat-based ablation therapies are unsuitable due to the tumor's stage, location, or extent. Photodynamic therapy (PDT), which involves delivering light-activated, tumor-killing photosensitizers, and percutaneous ethanol injection (PEI), which involves the direct injection of pure ethanol into tumor nodules, are two non-heat-based chemical ablative methods that have been proven safe with low adverse effects for unresectable tumors. We have investigated combining these two treatments using a new formulation known as BPD-EC-EtOH. This formulation includes three components: (1) benzoporphyrin derivative, a commonly used photosensitizer for PDT; (2) ethyl cellulose (EC), an FDA-approved polymer that forms a gel in the water phase and enhances drug retention; and (3) pure ethanol for PEI application. Here, we demonstrated the localization of BPD and confirmed that it retains its photochemical properties within the EC-EtOH gel in tissue-mimicking phantoms and in swine liver tissues. We also characterized EC's ability to act as a light-scattering agent, which effectively extends light propagation distance in both in vitro models and ex vivo porcine liver tissues, potentially overcoming the limitations of light penetration in pigmented organs. We then investigated the therapeutic effects of BPD-EC-EtOH using two well-established subcutaneous animal models of hepatocellular carcinoma and pancreatic ductal adenocarcinoma, both in single- and multi-cycle combination treatments, showing tumor-killing effects. These findings highlight the potential of BPD-EC-EtOH as a novel therapeutic approach, effective with either single or multi-cycle treatment sessions.

Tumors shift their metabolic needs to enable uncontrolled proliferation. Therefore, metabolic assessment of cancer patient sera provides a significant opportunity to noninvasively monitor disease progression and enable mechanistic understanding of the pathways that lead to response. Here, we show Raman spectroscopy (RS), a highly sensitive and label-free analytical tool, is effective in metabolic profiling across diverse cancer types in patient sera from both pancreatic ductal adenocarcinoma (PDAC) and locally advanced rectal cancer (LARC). We also combine metabolic data with proteomic signatures to predict treatment response. Our data show RS peaks successfully differentiate PDAC patients from healthy controls. Peaks associated with sugars, tyrosine, and DNA/RNA distinguish PDAC patients from chronic pancreatitis, an inflammatory condition that is notoriously difficult to discern from PDAC via current clinical approaches. Furthermore, our study is expanded to investigate response to chemoradiation therapy in LARC patient sera where at pre-treatment multiple metabolites including glycine, carotenoids, and sugars are jointly correlated to the neoadjuvant rectal (NAR) score indicative of poor prognosis. Via classical univariate AUC–ROC analysis, several RS peaks were found to have an AUC>0.7, highlighting the potential of RS in identifying key metabolites for differentiating complete and poor responders of treatment. Gene set enrichment analysis revealed enrichment of metabolic, immune, and DDR-related pathways associated with CRT response. Notably, RS-derived metabolites were significantly correlated with multiple immune signaling proteins and DDR markers, suggesting these distinct analytes converge to reflect systemic changes within the tumor microenvironment. By integrating metabolic, proteomic, and DDR data, we identified pre-treatment activation of galactose and glycerolipid metabolism, and post-treatment engagement of cell cycle and p53 signaling pathways. Our findings show that RS, when integrated with complementary protein marker analysis, holds the potential to bridge the translational divide enabling a clinically relevant approach for both diagnosis and predicting response in patient samples.

Malignant cerebral edema (MCE) represents a significant medical emergency characterized by unmanageable intracranial pressure (ICP), frequently arising as a consequence of traumatic brain injury (TBI) or ischemic stroke. Decompressive craniectomy (DC) is a prevalent surgical procedure employed to mitigate elevated ICP by excising a segment of the skull to enhance intracranial volume. Nevertheless, in patients suffering from MCE, the limited capacity for expansion of the scalp subsequent to DC may lead to sustained elevated ICP and complications including wound-edge necrosis, cerebrospinal fluid leakage, and infection. This investigation seeks to formulate a biocompatible, antibacterial, and anti-adhesive membrane intended for temporary scalp expansion following DC, thereby addressing these pressing concerns. The proposed membrane comprises polycaprolactone (PCL) augmented with silver nanoparticles (AgNPs) to confer antibacterial properties and is further immobilized with Mitomycin C (MMC) to minimize tissue adhesion, thereby facilitating more straightforward removal. The selection of PCL was predicated upon its remarkable mechanical strength and ductility, which make it suitable for withstanding intracranial edema and facilitating the suturing protocol. The AgNPs were synthesized through a green synthesis methodology employing epigallocatechin gallate (EGCG) to ensure environmental sustainability and the stability of the resultant nanoparticles. MMC, known for its anti-proliferative attributes, was affixed to the PCL surface via oxygen plasma treatment, thereby enhancing the anti-adhesive properties of the membrane. This study evaluates the mechanical characteristics, antibacterial effectiveness, anti-adhesive capabilities, and biocompatibility of the PCL/AgNPs/MMC membrane, thereby demonstrating its potential to improve outcomes in DC procedures by increasing intracranial volume and reducing postoperative complications.