Materials Today Bio最新文献

Immune checkpoint blockade (ICB) therapy, particularly PD1/PDL1 inhibition, has demonstrated success in bolstering durable responses in patients. However, the response rate remains below 30 %. In this study, we developed a polymeric bispecific antibody (BsAb) targeting PD1/PDL1 to enhance ICB therapy. Specifically, poly(_L-glutamic acid) (PGLU) was conjugated with a double cyclic Fc binding peptide, Fc-III-4C, through condensation reactions between the -COOH group of PGLU and the -NH₂ group of Fc-III-4C. This conjugate was then mixed with αPD1 and αPDL1 monoclonal antibodies (mAbs) in an aqueous solution. Mechanistically, the PD1/PDL1 BsAb (BsAb_αPD1+αPDL1) acts as a bridge between tumor cells and CD8⁺ T cells, continuously activating CD8⁺ T cells to a greater extent. This leads to significantly suppressed tumor growth and prolonged survival in a mouse model of colon cancer compared to treatment with either a single mAb or a mixture of free mAbs. The tumor suppression rate achieved by the BsAb_αPD1+αPDL1 was 90.1 %, with a corresponding survival rate of 83.3 % after 48 days. Thus, this study underscores the effectiveness of the BsAb_αPD1+αPDL1 as a synchronizing T cell engager and dual ICBs, offering theoretical guidance for clinical ICB therapy.

Guiding endogenous regeneration of bone defects using biomaterials and regenerative medicine is considered an optimal strategy. One of the effective therapeutic approaches involves using transgene-expressed stem cells to treat tissue destruction and replace damaged parts. Among the various gene editing techniques for cells, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) is considered as a promising method owing to the increasing therapeutic potential of cells by targeting specific sites. Herein, a vitamin D-incorporated poly(lactic-co-glycolic acid) (PLGA) scaffold with bone morphogenetic protein 2 (BMP2)/vascular endothelial growth factor (VEGF)-overexpressed tonsil-derived MSCs (ToMSCs) via CRISPR/Cas9 was introduced for bone tissue regeneration. The optimized seeding ratio of engineered ToMSCs on the scaffold demonstrated favorable immunomodulatory function, angiogenesis, and osteogenic activity in vitro. The multifunctional scaffold could potentially support stem cell in vivo and induce the transition from M1 to M2 macrophage with magnesium hydroxide and vitamin D. This study highlights the improved synergistic effect of a vitamin D-incorporated PLGA scaffold and a gene-edited ToMSCs for bone tissue engineering and regenerative medicine.

Inflammation is a major impediment to the healing of cartilage injuries, yet bioactive scaffolds suitable for cartilage repair in inflammatory environments are extremely rare. Herein, we utilized electrospinning to fabricate a two-dimensional nanofiber scaffold (2DS), which was then subjected to gas foaming to obtain a three-dimensional scaffold (3DS). 3DS was modified with metal phenolic networks (MPNs) composed of epigallocatechin gallate (EGCG) and strontium ions (Sr²⁺) to afford a MPNs-modified 3D scaffold (3DS-E). Gas-foamed scaffold exhibited multilayered structure conducive to cellular infiltration and proliferation. Compared to other groups, 3DS-E better preserved chondrocytes under interleukin (IL)-1β induced inflammatory environment, showing less apoptosis of chondrocytes and higher expression of cartilage matrix. Additionally, 3DS-E facilitated the regeneration of more mature cartilage in vivo, reduced cell apoptosis, and decreased the expression of pro-inflammatory cytokines.

Taken together, 3DS-E may offer an ideal candidate for cartilage regeneration.

Hydrogels are widely used to explore emerging minimally invasive strategies for intervertebral disc degeneration (IVDD) due to their suitability as drug and cell delivery vehicles. There has been no review of the latest research trends and strategies of hydrogel delivery systems in IVDD for the last decade. In this study, we identify the application trends and strategies in this field through bibliometric analysis, including aspects such as publication years, countries and institutions, authors and publications, and co-occurrence of keywords. The results reveal that the literature in this field has been receiving increasing attention with a trend of growth annually. Subsequently, the hotspots of hydrogels in this field were described and discussed in detail, and we proposed the “four core factors”, hydrogels, cells, cell stimulators, and microenvironmental regulation, required for a multifunctional hydrogel for IVDD. Finally, we discuss the popular and emerging mechanistic strategies of hydrogel therapy for IVDD in terms of five aspects: fundamental pathologic changes in IVDD, counteracting cellular senescence, counteracting cell death, improving organelle function, and replenishing exogenous cells. This study provides a reference and a new perspective for future research in this urgently needed field.

This study introduces the time-gated analysis of room-temperature phosphorescence (RTP) for the in-situ analysis of the visible and spectral information of photons. Time-gated analysis is performed using a microscopic system consisting of a spectrometer, which is advantageous for in-situ analysis since it facilitates the real-time measurement of luminescence signal changes. An RTP material hybridized with a DNA aptamer that targets a specific protein enhances the intensity and lifetime of phosphorescence after selective recognition with the target protein. In addition, time-gated analysis allows for the millisecond-scale imaging of phosphorescence signals, excluding autofluorescence, and improves the signal-to-background ratio (SBR) through the accumulation of signals. While collecting the time-gated images and spectra of RTP and autofluorescent materials simultaneously, we develop a method for obtaining phosphorescence signals by means of selective exclusion of autofluorescence signals in simulated or real cell conditions. It is confirmed that the accumulated time-gated analysis can provide ample information about luminescence signals for bioimaging and biosensing applications.

Lower urinary tract dysfunction (LUTD) is a prevalent condition characterized by symptoms such as urinary frequency, urgency, incontinence, and difficulty in urination, which can significantly impair patient's quality of life and lead to severe physiological complications. Despite the availability of diverse treatment options, including pharmaceutical and behavioral therapies, these approaches are not without challenges. The objective of this study was to enhance treatment options for LUTD by developing a wireless, battery-free device for managing bladder contractions. We designed and validated a compact, fully implantable, battery-free pulse generator using the magnetic induction coupling mechanism of wireless power transmission. Weighing less than 0.2 g and with a volume of less than 0.1 cubic centimeters, this device enables precise stimulation of muscles or neurons at voltages ranging from 0 to 10 V. Wireless technology allows real-time adjustment of key stimulation parameters such as voltage, duration, frequency, pulse width, and pulse interval. Our findings demonstrate that the device effectively controlled bladder contractions in mice when used to stimulate the Major Pelvic Ganglion (MPG). Additionally, the device successfully managed micturition in mice with bilateral transection of the pudendal nerve. In conclusion, the development of this innovative wireless pulse generator provides a safer and more cost-effective alternative to conventional battery-powered neurostimulators for bladder control, addressing the limitations of such devices. We anticipate that this novel technology will play a pivotal role in the future of electrical stimulation therapies for voiding dysfunctions.

Corneal opacity and deformation, which often require corneal transplantation for treatment, are among the leading causes of monocular blindness. To restore corneal clarity and integrity, there is a need for an artificial stroma that not only matches the transparency of donated human cornea but also effectively integrates to the corneal tissue. In this study, a transparent decellularized cornea was successfully developed using the high hydrostatic pressure method with processing conditions optimized for corneal decellularization. Biochemical analyses demonstrated the effective removal of cellular components from the transparent decellularized corneas, while preserving collagen and glycosaminoglycans. Proteome analysis also revealed that core matrisome and matrisome-associated proteins remained following decellularization, similar to the composition observed in untreated corneas. The light transmittance of the transparent decellularized corneas was 86.4 ± 1.5 % in the visible region, comparable to that of donated human corneas. No complications, such as angiogenesis, were observed following interlamellar corneal transplantation in rabbits. The grafts were almost imperceptible immediately following surgery and achieved complete transparency within a few days, becoming indistinguishable even under a microscope. The transparent decellularized cornea presented here has promising potential as a material for application in lamellar keratoplasty.

Diabetic foot ulcers, pressure ulcers, and bedsores can easily develop into chronic wounds with bacterial infections, complicating wound healing. This work reports a two-step strategy for treating infected chronic wounds. Firstly, LL37 mimetic peptide-W379 peptides were rapidly released to eliminate the bacterial biofilm on the wound. Then, 3D radially aligned nanofiber scaffolds loaded with W379 antimicrobial peptide and PDGF-BB were used to treat the wound to prevent bacterial infection recurrence and promote angiogenesis and granulation tissue regeneration, thereby accelerating wound healing. In the presented study, we found that the combined use of burst and controlled release of W379 antimicrobial peptide effectively clears the bacterial biofilm and prevents the recurrence of bacterial infection. Additionally, we found that the removal of the bacterial biofilm contributed to modulating the local inflammatory response from a pro-inflammatory type to a pro-regenerative type. Furthermore, the use of PDGF-BB significantly promotes neovascularization and granulation tissue regeneration in the wound bed, resulting in accelerating re-epithelialization and wound closure. Our study provides a promising treatment method for the repair of infected chronic wounds.

The adipogenic property of decellularized adipose-derived matrix (DAM) varies widely across reports, making it difficult to make a horizontal comparison between reports and posing challenges for the stable clinical translation of DAM. It is possibly due to differences in donor characteristics, but the exact relationship remains unclear. Despite extensive research on the differences between superficial and deep layers of abdominal subcutaneous fat, a main donor of DAM, little is known about their extracellular matrix (ECM) which is promising in regenerative medicine. In this study, we first confirmed the distinct compositional profiles and adipogenic potential between superficial and deep DAM (S-DAM and D-DAM). Both in vitro and in vivo assays confirmed superior adipogenic induction potential in S-DAM over D-DAM. Total amounts of ECM proteins like collagen and laminin were similar, however, the predominant types differed, with collagen I dominating S-DAM and collagen XIV prevailing in D-DAM. S-DAM was enriched with mitochondrial and immunological proteins, whereas D-DAM featured more neuronal, vascular, muscular, and endocrine-related proteins. More proteins involved in mRNA processing were found in D-DAM, with Protein-Protein Interaction (PPI) analysis revealing HNRNPA2B1, HNRNPA1, and HNRNPC as the most tightly interacting members. These findings not only deepen our comprehension of the structural and functional heterogeneity of adipose tissues but also become one of the reason for the large variability between batches of DAM products, providing guidance for constructing more efficient and stable bio-scaffolds.

Aristolochic acid I (AAI), a natural compound in aristolochia type Chinese medicinal herb, is generally acknowledged to have nephrotoxicity, which may be associated with mitophagy. Mitophagy is a cellular process with important functions that drive AAI-induced renal injury. Mitochondrial pH is currently measured by fluorescent probes in cell culture, but existing probes do not allow for in situ imaging of AAI-induced mitophagy in vivo. We developed a ratiometric fluorescent/PA dual-modal probe with a silicon rhodamine fluorophore and a pH-sensitive hemicyanine dye covalently linked via a short chain to obtain a FRET type probe. The probe was used to measure AAI-mediated mitochondrial acidification in live cells and in vivo. The Förster resonance energy transfer (FRET)-mediated ratiometric and bimodal method can efficiently eliminate signal variability associated with the commonly used one-emission and single detection mode by ratiometric two channels of the donor and acceptor. The probe has good water-solubility and low molecular weight with two positively charged, facilitating its precise targeting into renal mitochondria, where the fluorescent/PA changes in response to mitochondrial acidification, enabling dynamic and semi-quantitative mapping of subtle changes in mitochondrial pH in AAI-induced nephrotoxicity mouse model for the first time. Also, the joint use of L-carnitine could mitigate the mitophagy in AAI-induced nephrotoxicity.