Bioengineering & Translational Medicine最新文献

There is a clinical need for an effective nerve guidance conduit to treat peripheral nerve injuries. Many studies have explored different materials and active cues to guide neural regeneration, with some success. However, none have demonstrated a comparable or better functional recovery than the clinical standard autograft. Autografts are often insufficient for reconstruction of an injury to long nerves such as the sciatic or brachial plexus. Synthetic nerve guidance conduits (NGCs) have been investigated for these injuries to guide axonal regeneration and lead to functional recovery. We have designed a biologics-free hydrogel-based multi-channel conduit with defined microscale features to guide axonal outgrowth. To investigate extraneural vascular infiltration and its effects on functional recovery, we also designed a multi-microchannel conduit with defined regularly spaced micropores, orthogonal to the axon guidance channels. Using our custom-built Rapid Projection, Image-guided, Dynamic (RaPID) bioprinting system, we were able to fabricate each hydrogel conduit within minutes from a milliliter-volume prepolymer vat. With our state-of-the-art printing platform, we have achieved NGCs with a consistent channel wall width of 10 μm. We implanted the NGCs for 17 weeks in a murine sciatic nerve transection injury model. We assessed the functional recovery by dynamic gait analysis throughout the recovery period and by compound muscle action potential (CMAP) electrophysiology before NGC harvesting. Both the non-porous and micro-porous conduit groups led to functional nerve regeneration on par with the autograft group. Further, both conduit groups resulted in restoration of bulk motor function to pre-injury performance.

Inflammatory bowel disease (IBD) encompasses a group of intestinal disorders, primarily Crohn's disease (CD) and ulcerative colitis (UC), characterized by chronic inflammation of the digestive tract. Despite extensive research, the etiology of IBD remains largely unknown, and its progression and prognosis are unpredictable, often involving uncontrolled disease behavior. Current diagnostic and monitoring techniques, such as endoscopy, scoring systems, computed tomography, and ultrasound, provide valuable tools for assessing and monitoring disease progression; but are often used in conjunction with biomarker testing to achieve rapid and accurate results. Recent advances in biosensors, which integrate biorecognition elements with signal transduction platforms, offer immense potential to improve IBD diagnostics by enabling real-time, precise, and non-invasive detection of biomarkers such as C-reactive protein, calprotectin, and cytokines. This review examines existing IBD diagnostic techniques, their limitations, and the emerging role of biosensors in addressing these challenges. It explores the development of electrochemical and optical biosensors, highlights the key biomarkers utilized in these technologies, and identifies challenges and future opportunities for advancing next-generation biosensors for IBD diagnostics and monitoring. These innovations hold promise for enhancing IBD diagnosis, monitoring, and personalized disease management.

Diabetic foot ulcers (DFUs), a debilitating complication of diabetes, are exacerbated by persistent inflammation that disrupts wound repair. This study explores the therapeutic potential of antibiotic-loaded bone cement (ALBC) in modulating NLRP3 inflammasome activation and macrophage polarization to resolve chronic inflammation and accelerate healing. Using db/db diabetic mice with dorsal wounds and RAW264.7 macrophages under high-glucose conditions, we tested graded ALBC doses (high-dose ALBC, low-dose ALBC, and medium-dose ALBC) both in vivo and in vitro. Multi-modal analyses—including cytokine profiling (enzyme-linked immunosorbent assay), macrophage phenotyping (flow cytometry/immunofluorescence), and molecular pathway interrogation (reverse transcription quantitative PCR/Western blot)—revealed that ALBC dose-dependently suppressed NLRP3 inflammasome assembly, reduced IL-1β/IL-18 secretion, and skewed macrophages toward anti-inflammatory M2 phenotypes. Pharmacological NLRP3 activation reversed these effects, confirming pathway specificity. ALBC-treated wounds exhibited accelerated re-epithelialization, collagen deposition, and angiogenesis, correlating with attenuated systemic inflammation. Crucially, clinical DFU samples mirrored preclinical findings, showing NLRP3 downregulation and M2 dominance in ALBC-responsive cases. These results demonstrate that ALBC orchestrates immunometabolic reprogramming by silencing NLRP3-driven inflammation and fostering pro-reparative macrophage responses. By bridging biomaterial engineering with immunomodulation, this work advances a translatable strategy for refractory DFU management, offering a dual-action therapeutic platform that combines localized antibiotic delivery with microenvironmental immune reset.

Malignant brain tumors, particularly glioblastoma multiforme (GBM), are aggressive and fatal cancers. The clinical efficacy of current standard-of-care treatments against brain tumors has been minimal, with no significant improvement over the past 30 years. Driven by the success of chimeric antigen receptor (CAR)-T cells in the clinic for treating certain types of cancer, adoptive cell therapies have been of interest as a hopeful therapeutic modality for brain tumors. Clinical trials of GBM-targeting cell therapies, including CAR-T cells, have been initiated; however, none of them have been approved yet, and new challenges have emerged from the completed clinical trials. These issues are being addressed in ongoing clinical trials and recent preclinical research efforts. Herein, we present an overview of the clinical landscape of cell therapies against brain tumors. We analyze past and active 203 clinical trials focusing on cell therapies for brain tumors, discuss limitations for their clinical translation, and highlight emerging approaches to address these challenges. In addition, we review select preclinical studies that show promise to improve the therapeutic efficacy of therapeutic cells on brain tumors and discuss future prospects.

Adalimumab (Humira) represents a major advance in rheumatoid arthritis (RA) therapy. However, with long-term administration of Adalimumab, anti-idiotypic antibody (anti-Id Ab) accelerates the Adalimumab clearance rate and reduces the therapeutic effect. To avoid the interference of anti-Id Ab, we used an autologous hinge region as a spatial-hindrance-based Ab lock and connected it to the N-terminal of the light chain and heavy chain via substrate peptides (MMP-2/9) to cover the CDR binding site of Adalimumab to generate pro-Adalimumab. The Ab lock masks the complementarity-determining regions (CDRs) of Adalimumab, thus avoiding interference from anti-Id Ab. Pro-Adalimumab demonstrated a 241.6 times weaker binding ability to TNFɑ than Adalimumab. In addition, pro-Adalimumab showed a 46.6-fold greater blocking of anti-Adalimumab Id Ab in comparison to Adalimumab prior to activation. Similar results were observed with other clinical antibodies, such as pro-Infliximab (anti-TNFɑ Ab) and pro-Nivolumab (anti-PD-1). Furthermore, pro-Adalimumab maintained consistent pharmacokinetics regardless of the presence of anti-Adalimumab Id antibodies, while Adalimumab showed a 49% clearance increase, resulting in a near complete loss of function. Additionally, pro-Adalimumab was able to avoid neutralization and efficiently reduce RA progression in the presence of anti-Adalimumab Id Ab in vivo. In summary, we developed a pro-Adalimumab that avoids interference from anti-Id Abs, thereby addressing the biggest issue limiting clinical efficacy. The findings enclosed herein may have potentially broad application in antibody therapies.

An abdominal aortic aneurysm (AAA) is a life-threatening vascular condition characterized by the dilation of the abdominal aorta, with ferroptosis playing a significant role in its pathogenesis. This study investigates the therapeutic potential of engineering biomimetic nanovesicles to deliver phosphatidylethanolamine-binding protein 1 (PEBP1) mRNA for inhibiting ferroptosis in vascular smooth muscle cells (VSMCs) and preventing AAA progression. Differential gene expression analysis of the AAA transcriptomic dataset GSE57691 identified 243 differentially expressed genes (DEGs), intersecting with 12 ferroptosis-related genes. Single-cell analysis of dataset GSE237230 highlighted PEBP1 as a key gene in VSMCs. Overexpression of PEBP1 in VSMCs enhanced proliferation, reduced reactive oxygen species (ROS) and iron levels, and inhibited apoptosis and ferroptosis via the NRF2/GPX4 axis. The engineered biomimetic nanovesicles demonstrated significant uptake by VSMCs and effective delivery of PEBP1 mRNA. In vivo studies confirmed that these nanovesicles substantially inhibited AAA progression in mice. This study presents a novel bioengineering approach for AAA treatment by targeting ferroptosis through PEBP1 mRNA delivery, offering a promising molecular strategy for the prevention and management of AAA.

Current ectopic implantation has shown limited efficacy in promoting reinnervation of the nigrostriatal pathway, which is critically affected in Parkinson's disease (PD). Homotopic transplantation, on the other hand, may facilitate physiological cell rewiring of the basal ganglia, potentially improving PD symptoms. This study aimed to evaluate the efficacy and safety of homotopically engrafting human induced pluripotent stem cells (hiPSCs)-derived midbrain organoids into the substantia nigra of PD rats. A rat model of PD was induced using 6-hydroxydopamine (6-OHDA) and homotopically transplanted into the lesioned SN with hiPSC-derived hMOs. The engrafted hMOs survived and continually mature in host brains, and were mainly differentiated into dopaminergic lineage neurons, part of which presented TH⁺ fibers. Behavioral evaluation demonstrated that transplantation of hMOs gradually reverse the motor disorder caused by 6-OHDA lesioning by 22% at week 5 and 35% by week 10 post-transplantation, respectively. No tumor formation or migration was detected in either subcutaneous space or vital organs following 10 weeks implantation. These findings support the efficacy and safety of homotopical hMOs transplantation, offering a promising cell-based strategy for treating Parkinson's disease.

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.

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.