Biomaterials最新文献

Developing drug delivery systems capable of achieving deep tumor penetration is a challenging task, yet there is a significant demand for such systems in cancer treatment. Hitchhiking on tumor-derived extracellular vesicles (EVs) represents a promising strategy for enhancing drug penetration into tumors. However, the limited drug assembly on EVs restricts its further application. Here, we present a novel approach to efficiently attach antitumor drugs to EVs using an engineered cell membrane-based vector. This vector includes the AS1411 aptamer for tumor-specific targeting, the vesicular stomatitis virus glycoprotein (VSV-G) for tumor cell membrane fusion, and a photosensitizer as the therapeutic agent while ensuring optimal drug encapsulation and stability. Upon injection, photosensitizers are firstly transferred to the tumor cell membrane and subsequently piggybacked onto EVs with the inherent secretion process. By hitchhiking with EVs, photosensitizers can be transferred layer by layer deep into the solid tumors. The results suggest that this EVs-hitchhiking strategy enables photosensitizers to penetrate deeply into tumor tissue, thereby enhancing the efficacy of phototherapy. This study offers broad application prospects for delivering drugs deeply into tumor tissues.

Fibroblasts are cells responsible for producing extracellular matrix (ECM) components, which provides physical support for organs. Although these mesenchymal cells are responsive to mechanical cues in their environment, the permanence of these mechanophenotypes is not well defined. We investigated the mechanomemory of lung fibroblasts and determined how switching culture conditions modulate cell responses and function. Primary murine lung fibroblasts were isolated and cultured on 2D tissue culture plates or within 3D collagen hydrogels and were then passaged within the same or opposite culture condition to assess changes in gene expression, protein production, fibroblast subpopulation, contractile behavior, and traction forces. Compared to fibroblasts isolated on 2D tissue culture plates, fibroblasts within 3D hydrogels exhibited a decreased activation phenotype including reduced contraction profiles, diminished cell traction forces and decreased αSMA gene expression. Cells initially isolated via 2D culture and then cultured in 3D hydrogels exhibited a reversal in activation phenotype as measured by gene expression and contraction profiles. Bulk RNAseq identified groups of genes that exhibit reversible and non-reversable expression patterns. Overall, these findings indicate that lung fibroblasts have a mechanical memory that is altered by culture condition and can be reversible through precondition of cells within a softer 3D microenvironment.

The pathogenesis of osteoarthritis (OA), a disease causing severe medical burden and joint deformities, remains unclear. Chondrocyte death and osteochondral injury caused are the main pathological changes in OA. Thus, inhibiting chondrocyte death and repairing defective osteochondral are two important challenges in the treatment of OA. In this study, we found morphological changes consistent with cell pyroptosis in OA cartilage tissues. To inhibit chondrocyte pyroptosis and delay the progression of OA, we proposed to use decellularized extracellular matrix (dECM) and gelatin methacrylate (GelMA) to form a composite hydrogel GelMA/dECM. Regarding osteochondral defect repair, our proposed treatment strategy was hydrogel combined with microfracture (MF) surgery. MF established a biological link between the osteochondral defect and the bone-marrow cavity, prompting the recruitment of bone-marrow mesenchymal stem cells (BMSCs) to the osteochondral defect site, and the retained biopeptides in the hydrogel regulate the polarization of the BMSCs into hyaline cartilage, accelerating the repair of the defect. In vitro/vivo experiments and RNA sequencing analyses demonstrated that GelMA/dECM inhibited the occurrence of chondrocyte pyroptosis and delayed OA disease progression. Hydrogel also recruited numerous of BMSCs and contributed to chondrogenic differentiation, accelerating the in situ repair of defective osteochondral combined with MF. Collectively, GelMA/dECM composite hydrogel inhibited cartilage pyroptosis and reduced the pathway of chondrocyte death. Moreover, the hydrogel combined with microfracture technique could accelerate the repair of osteochondral defects. This is a groundbreaking attempt by tissue engineering, cell biology, and clinical medicine.

Postoperative tumor treatment necessitates a delicate balance between eliminating residual tumor cells and promoting surgical wound healing. Addressing this challenge, we harness the innovation and elegance of nature's ingenuity to develop a butterfly-wing-inspired photoactive nanofiber patch (WingPatch), aimed at advancing postoperative care. WingPatch is fabricated using a sophisticated combination of electrostatic spinning and spraying techniques, incorporating black rice powder (BRP) and konjac glucomannan (KGM) into a corn-derived polylactic acid (PLA) nanofiber matrix. This fabrication process yields a paclitaxel-infused porous nanofiber architecture that mirrors the delicate patterns of butterfly wings. Meanwhile, all-natural composites have been selected for their strategic roles in postoperative recovery. BRP offers the dual benefits of photothermal therapy and antibacterial properties, while KGM enhances both antibacterial effectiveness and tissue regeneration. Responsive to near-infrared light, WingPatch ensures robust tissue adhesion and initiates combined photothermal and chemotherapeutic actions to effectively destroy residual tumor cells. Crucially, it simultaneously prevents infections and promotes wound healing throughout the treatment process. Its effectiveness has been confirmed by animal studies, and WingPatch significantly improves treatment outcomes in both breast and liver tumor models. Thus, WingPatch exemplifies our dedication to leveraging natural world's intricate patterns and inventiveness to propel postoperative care forward.

Erectile dysfunction (ED) is a common male sexual disorder characterized by repeated or persistent difficulty in achieving or maintaining an erection. It can arise from various factors, with cavernous nerve injury (CNI) from radical prostatectomy being a predominant cause of iatrogenic ED, posing significant clinical concerns. The complexity of cavernous tissue damage in CNI-induced ED (CNIED) often results in poor efficacy and resistance to conventional vascular ED treatments. To address CNI-induced ED, this study developed a system of magnetic mesoporous silica nanoparticles (MSNs) loaded with peptides for targeted treatment. Core-shell Fe₃O₄-coated MSNs were used as drug carriers and loaded with RADA16-I/RAD-RGI peptides (P_D) to create a neurotrophic microenvironment to treat peripheral nerve defects. Furthermore, the neuro-targeting peptide HLNILSTLWKYR (P_T) was grafted onto MSNs. The in vivo therapeutic effect was evaluated using a rat bilateral cavernous nerve injury (BCNI) model. The results showed that the neuro-targeted Fe₃O₄@SiO₂-P_T-P_D nanoparticles significantly promoted regeneration of the cavernous nerve and restored erectile function. This promising strategy offers significant clinical potential for treating CNI-induced ED. Nanomedicine technology has the potential to not only improve treatment outcomes but also reduce side effects in healthy cells, paving the way for more accurate targeted repair of cavernous nerve damage.

Injuries to the central nervous system, such as stroke and traumatic spinal cord injury, result in an aggregate scar that both limits tissue degeneration and inhibits tissue regeneration. The aggregate scar includes chondroitin sulfate proteoglycans (CSPGs), which impede cell migration and axonal outgrowth. Chondroitinase ABC (ChASE) is a potent yet fragile enzyme that degrades CSPGs, and thus may enable tissue regeneration. ChASE37, with 37-point mutations to the native enzyme, has been shown to be more stable than ChASE, but its efficacy has never been tested. To answer this question, we investigated the efficacy of ChASE37 first in vitro using human cell-based assays and then in vivo in a rodent model of stroke. We demonstrated ChASE37 degradation of CSPGs in vitro and the consequent cell adhesion and axonal sprouting now possible using human induced pluripotent stem cell (hiPSC)-derived neurons. To enable prolonged release of ChASE37 to injured tissue, we expressed it as a fusion protein with a Src homology 3 (SH3) domain and modified an injectable, carboxymethylcellulose (CMC) hydrogel with SH3-binding peptides (CMC-bp) using inverse electron-demand Diels−Alder chemistry. We injected this affinity release CMC-bp/SH3-ChASE37 hydrogel epicortically to endothelin-1 stroke-injured rats and confirmed bioactivity via degradation of CSPGs and axonal sprouting in and around the lesion. With CSPG degradation shown both in vitro by greater cell interaction and in vivo with local delivery from a sustained release formulation, we lay the foundation to test the potential of ChASE37 and its delivery by local affinity release for tissue regeneration after stroke.

Activation of the stimulator of interferon genes (STING) pathway by radiotherapy (RT) has a significant effect on eliciting antitumor immune responses. The generation of hydroxyl radical (·OH) storm and the sensitization of STING-relative catalytic reactions could improve radiosensitization-mediated STING activation. Herein, multi-functional radiosensitizer with oxygen vacancies depended mimicking enzyme-like activities was fabricated to produce more dsDNA which benefits intracellular 2′, 3′-cyclic GMP-AMP (cGAMP) generation, together with introducing exogenous cGAMP to activate immune response. MnO₂@CeO_x nanozymes present enhanced superoxide dismutase (SOD)-like and peroxidase (POD)-like activities due to induced oxygen vacancies accelerate the redox cycles from Ce⁴⁺ to Ce³⁺ via intermetallic charge transfer. CeO_x shells not only serve as radiosensitizer, but also provide the conjugation site for AMP/GMP to form MnO₂@CeO_x-GAMP (MCG). Upon X-ray irradiation, MCG with SOD-like activity facilitates the conversion of superoxide anions generated by Ce-sensitization into H₂O₂ within tumor microenvironment (TME). The downstream POD-like activity catalyzes the elevated H₂O₂ into a profusion of ·OH for producing more damage DNA fragments. TME-responsive decomposed MCG could supply exogenous cGAMP, meanwhile the releasing Mn²⁺ improve the sensitivity of cyclic GMP-AMP synthase to dsDNA for producing more cGAMP, resulting in the promotion of STING pathway activation.

Pro-fibrotic M2-like macrophages are widely implicated in the pathogenesis and progression of lung fibrosis due to their production of pro-fibrotic growth factors and cytokines. Yeast beta-glucan (YBG) microparticles have shown potential as immunomodulators that can convert macrophage polarization from a pro-fibrotic phenotype to an anti-fibrotic phenotype through the engagement of the Dectin-1 receptor. However, the processing conditions used to fabricate YBG microparticles can lead to unpredictable immunomodulatory effects. Herein, we report the use of Pressurized Gas eXpanded liquids (PGX) Technology® to fabricate YBG (PGX-YBG) microparticles with higher surface areas, lower densities, and smaller and more uniform size distributions compared to commercially available spray-dried YBGs. PGX-YBG is shown to activate Dectin-1 more efficiently in vitro while avoiding significant TLR 2/4 activation. Furthermore, PGX-YBG microparticles effectively modulate M2-like fibrosis-inducing murine and human macrophages into fibrosis-suppressing macrophages both in vitro as well as in ex vivo precision-cut murine lung slices, suggesting their potential utility as a therapeutic for addressing a broad spectrum of fibrotic end-point lung diseases.

Wound healing concerns almost all bed-side related diseases. With our increasing comprehension of healing nature, the physical and chemical natures behind the wound microenvironment have been decoupled. Wound care demands timely screening and prompt diagnosis of wound complications such as infection and inflammation. Biosensor by the way of exhaustive collection, delivery, and analysis of data, becomes indispensable to arrive at an ideal healing upshot and controlling complications by capturing in-situ wound status. Electrochemical based sensors carry some potential unstable performance subjected to the electrical circuitry and power access and contamination. The colorimetric sensors are free from those concerns. We report that microsensors designed from O/W/O of capillary fluids can continuously monitor wound temperature, pH and glucose concentration. We combined three different types of microgels to encapsulate liquid crystals of cholesterol, nontoxic fuel litmus and two glucose-sensitizing enzymes. A smartphone applet was then developed to convert wound healing images to RGB of digitalizing data. The microgel dressing effectively demonstrates the local temperature change, pH and glucose levels of the wound in high resolution where a microgel is a 'pixel’. They are highly responsive, reversible and accurate. Monitoring multiple physicochemical and physiological indicators provides tremendous potential with insight into healing processing.