Acta biomaterialia最新文献

Cell therapy is a promising strategy for treating neurological pathologies but requires invasive methods to bypass the blood-brain barrier restrictions. The nose-to-brain route has been presented as a direct and less invasive alternative to access the brain. The primary limitations of this route are low retention in the olfactory epithelium and poor cell survival in the harsh conditions of the nasal cavity. Thus, using chitosan-based hydrogel as a vehicle is proposed in this work to overcome the limitations of nose-to-brain cell administration. The hydrogel's design was driven to achieve gelification in response to body temperature and a mucosa-interacting chemical structure biocompatible with cells. The hydrogel showed a < 30 min gelation time at 37 °C and >95 % biocompatibility with 2D and 3D cultures of mesenchymal stromal cells. Additionally, the viability, stability, and migration capacity of oligodendrocyte precursor cells (OPCs) within the hydrogel were maintained in vitro for up to 72 h. After the intranasal administration of the OPCs-containing hydrogel, histological analysis showed the presence of viable cells in the nasal cavity for up to 72 h post-administration in healthy athymic mice. These results demonstrate the hydrogel's capacity to increase the residence time in the nasal cavity while providing the cells with a favorable environment for their viability. This study presents for the first time the use of thermosensitive hydrogels in nose-to-brain cell therapy, opening the possibility of increasing the delivery efficiency in future approaches in translational medicine. STATEMENT OF SIGNIFICANCE: This work highlights the potential of biomaterials, specifically hydrogels, in improving the effectiveness of cell therapy administered through the nose. The nose-to-brain route has been suggested as a non-invasive way to directly access the brain. However, delivering stem cells through this route poses a challenge since their viability must be preserved and cells can be swept away by nasal mucus. Earlier attempts at intranasal cell therapy have shown low efficiency, but still hold promise to the future. The hydrogels designed for this study can provide stem cells with a biocompatible environment and adhesion to the nasal atrium, easing the successful migration of viable cells to the brain.

Pulmonary air leaks are amongst the most common complications in lung surgery. Lung sealants are applied to the organ surface and need to synchronously stretch with the visceral pleura, the layer of tissue which encompasses the lung parenchymal tissue. These adhesives are commonly tested on pig and rat lungs, but applied to human lungs. However, the unknown mechanics of human lung visceral pleura undermines the clinical translatability of such animal-tested sealants and the absence of how pig and rat lung visceral pleura compare to human tissues is necessary to address. Here we quantify the biaxial planar tensile mechanics of visceral pleura from healthy transplant-eligible and smoker human lungs for the first time, and further compare the material behaviors to pig and rat lung visceral pleura. Initial and final stiffness moduli, maximum stress, low-to-high strain transition, and stress relaxation are analyzed and compared between and within groups, further considering regional and directional dependencies. Visceral pleura tissue from all species behave isotropically, and pig and human visceral pleura exhibits regional heterogeneity (i.e. upper versus lower lobe differences). We find that pig visceral pleura exhibits similar initial stiffness moduli and regional trends compared to human visceral pleura, suggesting pig tissue may serve as a viable animal model candidate for lung sealant testing. The outcomes and mechanical characterization of these scarce tissues enables future development of biomimetic lung sealants for improved surgical applications. STATEMENT OF SIGNIFICANCE: Surgical lung sealants must synchronously deform with the underlying tissue and with each breath to minimize post-operative air leaks, which remain the most frequent complications of pulmonary intervention. These adhesives are often tested on pig and rat lungs, but applied to humans; however, the material properties of human lung visceral pleura were previously unexplored. Here, for the first time, the mechanics of human visceral pleura tissue are investigated, further contrasting rarely acquired donated lungs from healthy and smoking individuals, and additionally, comparing biaxial planar material characterizations to animal models often employed for pulmonary sealant development. This fundamental material characterization addresses key hindrances in the advancement of biomimetic sealants and evaluates the translatability of animal model experiments for clinical applications.

The integration of biomaterials in medical applications triggers the foreign body response (FBR), a multi-stage immune reaction characterized by the formation of foreign body giant cells (FBGCs). Originating from the fusion of monocyte/macrophage lineage cells, FBGCs are pivotal participants during tissue-material interactions. This review provides an in-depth examination of the molecular processes during FBGC formation, highlighting signaling pathways and fusion mediators in response to both exogenous and endogenous stimuli. Moreover, a wide range of material-specific characteristics, such as surface chemical and physical properties, has been proven to influence the fusion of macrophages into FBGCs. Multifaceted biological activities of FBGCs are also explored, with emphasis on their phagocytic capabilities and extracellular secretory functions, which profoundly affect the vascularization, degradation, and encapsulation of the biomaterials. This review further elucidates the heterogeneity of FBGCs and their diverse roles during FBR, as demonstrated by their distinct behaviors in response to different materials. By presenting a comprehensive understanding of FBGCs, this review intends to provide strategies and insights into optimizing biocompatibility and the therapeutic potential of biomaterials for enhanced stability and efficacy in clinical applications. STATEMENT OF SIGNIFICANCE: As a hallmark of the foreign body response (FBR), foreign body giant cells (FBGCs) significantly impact the success of implantable biomaterials, potentially leading to complications such as chronic inflammation, fibrosis, and device failure. Understanding the role of FBGCs and modulating their responses are vital for successful material applications. This review provides a comprehensive overview of the molecules and signaling pathways guiding macrophage fusion into FBGCs. By elucidating the physical and chemical properties of materials inducing distinct levels of FBGCs, potential strategies of materials in modulating FBGC formation are investigated. Additionally, the biological activities of FBGCs and their heterogeneity in responses to different material categories in vivo are highlighted in this review, offering crucial insights for improving the biocompatibility and efficacy of biomaterials.

Dentin hypersensitivity (DH) manifests as sharp and uncomfortable pain due to the exposure of dentinal tubules (DTs) following the erosion of tooth enamel. Desensitizing agents commonly used in clinical practice have limitations such as limited depth of penetration, slow remineralization and no antimicrobial properties. To alleviate these challenges, our study designed a lactoferrin-derived amyloid nanofilm (PTLF nanofilm) inspired by the saliva-acquired membrane (SAP). The nanofilm utilises Tris(2-carboxyethyl)phosphine (TCEP) to disrupt the disulfide bonds of lactoferrin (LF) under physiological conditions. The PTLF nanofilm modifies surfaces across various substrates and effectively prevents the early and stable adhesion of cariogenic bacteria, such as Streptococcus mutans and Lactobacillus acidophilus. Simultaneously, it adheres rapidly and securely to demineralized dentin surfaces, facilitating in-situ remineralization of HAP through a simple immersion process. This leads to the formation of a remineralized layer resembling natural dentin, with an occlusion depth of dentinal tubules exceeding 80 µm after three days. The in vivo and vitro results confirm that the PTLF nanofilm possesses good biocompatibility and its ability to exert simultaneous antimicrobial effects and dentin remineralization. Accordingly, this innovative bifunctional PTLF amyloid coating offers promising prospects for the management of DH-related conditions. STATEMENT OF SIGNIFICANCE.

Photodynamic therapy (PDT) has attracted widespread attention from researchers as an emerging cancer treatment method. There have been many reports on various types of NIR-II photosensitizers for imaging and treatment of tumor sites. However, there are few reports on the development of NIR-II organic small molecule photosensitizers that have intelligent response to the tumor microenvironment, precise imaging, real-time treatment, and high biocompatibility. In this work, we developed a series of NIR-II photosensitizers (RBTs) with near-infrared excitation, good photostability, and large Stokes shift. Among them, RBT-Br exhibited higher reactive oxygen species (ROS) generation efficiency due to the introduction of halogen heavy atoms to enhance intersystem crossing (ISC). It is noteworthy that RBT-Br can generate singlet oxygen (¹O₂) and superoxide anion radicals (^•O₂^-) simultaneously under 730 nm laser. Subsequently, we used molecular engineering technology to construct three pH-responsive NIR-II photosensitizers (RBT-pHs) by utilizing the closure of the lactam ring, among which RBT-pH-1 (pK_a = 6.78) is able to be directionally activated under the stimulation of tumor micro-acid environment, with its fluorescence emission window reaching 933 nm. Subsequently, RBT-pH-1 NPs encapsulated in DSPE-mPEG_5k were applied for PDT treatment of mouse tumors. The results showed that RBT-pH-1 NPs were activated by the acidic tumor microenvironment and generated ROS under laser excitation, exhibiting precise tumor imaging and significant tumor growth inhibition. We look forward to these multifunctional NIR-II organic small molecule photosensitizers providing a more efficient approach for clinical treatment of tumors. STATEMENT OF SIGNIFICANCE: A reversible pH-switchable NIR-II nano-photosensitizer RBT-pH-1 NPs (pK_a = 6.76) is developed for precise imaging and PDT therapy of mouse tumors, which can be effectively used for targeted enrichment and activation of tumor micro-acid environments. The results show that this NIR-II photosensitizer generates ROS through tumor micro-acid environment stimulation and laser triggering, showing precise tumor imaging guidance and significant tumor growth inhibition.

Traditional adhesive hydrogels perform well in tissue adhesion but they fail to prevent postoperative tissue adhesion. To address this challenge, a biodegradable Janus adhesive hydrogel (J-AH) was designed and fabricated by the assembly of three different functional layers including anti-adhesive layer, reinforceable layer, and wet tissue adhesive layer. Each layer of J-AH serves a specific function: the top zwitterionic polymeric anti-adhesive layer shows superior resistance to cell/protein and tissue adhesion; the middle poly(vinyl alcohol)/tannic acid reinforceable matrix layer endows the hydrogel with good mechanical toughness of ∼2.700 MJ/m³; the bottom poly(acrylic acid)/polyethyleneimine adhesive layer imparts tough adhesion (∼382.93 J/m² of interfacial toughness) to wet tissues. In the rat liver and femoral injury models, J-AH could firmly adhere to the bleeding tissues to seal the wounds and exhibit impressive hemostatic efficiency. Moreover, in the in vivo adhesion/anti-adhesion assay of J-AH between the defected cecum and peritoneal walls, the top anti-adhesive layer can effectively inhibit undesired postoperative abdominal adhesion and inflammatory reaction. Therefore, this research may present a new strategy for the design of advanced bio-absorbable Janus adhesive hydrogels with multi-functions including tissue adhesion, anti-postoperative adhesion and biodegradation. STATEMENT OF SIGNIFICANCE: Despite many adhesive hydrogels with tough tissue adhesion capability have been reported, their proclivity for undesired postoperative adhesion remains a serious problem. The postoperative adhesion may lead to major complications and even endanger the lives of patients. The injectable hydrogels can cover the irregular wound and suppress the formation of postoperative adhesion. However, due to the lack of adhesive properties with tissue, it is difficult for the hydrogels to maintain on the wound surface, resulting in poor anti-postoperative adhesion effect. Herein, we design a Janus adhesive hydrogel (J-AH). J-AH integrates together robust wet tissue adhesion and anti-postoperative adhesion. Therefore, this research may present a new strategy for the design of advanced bio-absorbable Janus adhesive hydrogels.

Bioactive glasses (BGs) bond with bone by forming hydroxy carbonate apatite (HCA) upon reaction in physiological fluid, a phenomenon known as bioactivity. BGs structural network connectivity determines their bioactivity. Sol-gel BGs are synthesized through the hydrolysis and condensation of metal alkoxide precursors in the presence of a catalyst, in aqueous environments. Several sol-gel synthesis parameters directly impact BG network connectivity: pH (i.e. acid or basic catalysis), water to alkoxide ratio (R_w), alkoxide type and presence of dopant ions. However, the relationship between bioactivity and these parameters remains surprisingly unexplored. This study highlights the relationship between synthesis pH, R_w, network connectivity and bioactivity in silica-based sol-gel BGs and BGs doped with titanium (Ti) ions (TiBGs), the latter selected for their known ability to enhance network connectivity. BGs and TiBGs are synthesized with various R_w values under acidic and basic conditions, and their bioactivity is assessed in simulated body fluid for 7 days. Increasing R_w decreases network connectivity and increases bioactivity of BGs with high network connectivity, as observed for base-catalyzed BGs and for both acid and base catalyzed TiBGs, but not in BGs with lower connectivity as evidenced in acid-catalyzed BGs. Basic catalysis of TiBGs prevents crystalline TiO₂ domain formation, which was instead consistently observed in TiBGs synthesized under acidic catalysis. These findings help the design of BGs for applications where ion release needs to be enhanced even in the presence of dopants that slow down HCA formation, and of BGs with specific properties, e.g. TiO₂-containing BGs with potential bactericidal activity. STATEMENT OF SIGNIFICANCE: Bioactive glasses (BGs) bond with bone by dissolving and forming hydroxycarbonate apatite (HCA) on their surface, offering applications in medicine and dentistry. BG's network connectivity influences its dissolution rate, and hence HCA formation. While solution-gelation (sol-gel) is commonly used for BG production, the effect of sol gel synthesis parameters on HCA formation remains unexplored. We studied the relationship between synthesis parameters (water-to-alkoxide ratio (R_w), catalyst, and dopant ions, particularly titanium), BG network connectivity, and HCA formation. We find that increasing R_w with any catalyst enhances HCA formation, particularly in glasses with high network connectivity. This understanding allows tailoring BG synthesis for different applications, e.g. those requiring doping with ions that increase network connectivity and fills a crucial gap in BG literature.

The immunosuppressive tumor microenvironment, such as lactic acid and matrix metalloproteinases (MMPs) overexpression, has been well confirmed to be adverse for tumor therapy. In current study, a tumor microenvironment modulatory hydrogel was successfully developed to treat melanoma by taking advantage of the synergistic effects of nano-hydroxyapatite (nHA) with well-documented selective anti-tumor action, lactate dehydrogenase A inhibitor (R)-GNE-140 (GNE), and matrix metalloproteinase-2 (MMP-2) sensitive peptide. The hydrogel was acquired by the reaction of 4-arm-polyethylene glycol-maleic anhydride (4-arm-PEG-MAL) and MMP-2 sensitive peptide (CC-14), in which nHA and GNE were co-encapsulated physically. The in vitro degradation tests confirmed the accelerated release of nHA and GNE from the hydrogel under less-acidic (pH 6.8) and MMP-2 containing conditions compared to those neutral or without MMP-2 conditions, demonstrating the pH and MMP-2 responsive properties of as-prepared hydrogel. Findings from in vitro cell experiments revealed that the hydrogel could stop the proliferation of melanoma cells by stacking cell cycle via lactic acid metabolic dysregulation and boosting cell apoptosis via nHA direct killing effect. Moreover, after hydrogel treatment, the rate of migration and aggressiveness of melanoma cells both reduced significantly. An in vivo anti-melanoma study showed that the hydrogel could inhibit tumor growth significantly and result in more CD8⁺ T cells and antigen-presenting cells but less T_reg cells infiltration, ultimately leading to an enhanced therapeutic efficacy. As thus, the fabricated hydrogel demonstrated great promise for treating melanoma and could be a new potent strategy for efficient melanoma therapy. STATEMENT OF SIGNIFICANCE: Nano-hydroxyapatite (nHA) has the capability of selectively killing cancer cells. The study reported a tumor microenvironment (TME) modulatory hydrogel with the goal of enhancing melanoma therapy efficacy by combining nHA administration with immunosuppressive microenvironment modulation. The hydrogel demonstrated pH and MMP-2 sensitivity. Hence, controlled release of nHA and lactate dehydrogenase A inhibitor (GNE) could be observed, and in situ MMP-2 consumption at the tumor site occurred. The hydrogel effectively inhibited the growth of melanoma cells. Furthermore, hydrogel increased the production of CD8⁺ T cells and antigen-presenting cells while decreasing the infiltration of T_reg cells at the tumor site. This could transform the initial "cold" tumor into a "hot" tumor, ultimately resulting in an enhanced therapeutic effect.

Nerve-derived factors have attracted attention in bone regeneration therapy due to their ability to promote bone regeneration and nerve innervation. Mesenchymal stem cells transported to target sites promote osteogenesis. However, there are few reports on the effects of neural stem cells on bone regeneration. Therefore, the aim of this study was to investigate the role of neural stem cells in osteogenesis. Here, embryoid bodies (EB) or primary neurospheres (1NS) were generated using mouse induced pluripotent stem cells (iPS cells), which were then seeded onto gelatin (Gel) sponges. The seeded Gel sponges were then transplanted into mouse calvarial bone defects. We noted that 1NS-seeded Gel promoted bone regeneration and the presence of tartrate-resistant acid phosphatase (TRAP)-positive cells, whereas the EB-seeded Gel did not. RNA-sequencing of the 1NS-seeded and EB seeded Gels showed an upregulation of the transforming growth factor (TGF)-β signaling pathway in the 1NS-seeded Gel group. Immunostaining confirmed the presence of Id3 positive cells in mice with bone defects treated with the 1NS-seeded Gel. These findings suggest that the transplantation of neural stem cells may contribute to the promotion of bone regeneration. STATEMENT OF SIGNIFICANCE: This study aimed to investigate whether neural stem cells, when seeded in Gel sponges, promoted bone regeneration. It has been well documented that bone is tightly linked with the nervous systems. Bioscaffolds comprising factors that promote innervation and bone regeneration have been investigated for use in bone therapy. However, there is limited research on the use of neural stem cells for promoting bone formation. To assess this relationship, we conducted both in vivo and in vitro assays to determine whether neural stem cells promoted bone formation. We noted that 1NS-seeded Gel sponges promoted bone formation significantly in mice with calvarial defects after 4 weeks. This study provides a novel approach of neural stem cells for bone therapy.

Approximately 25% of newly diagnosed AML patients display an internal tandem duplication (ITD) in the fms-like tyrosine kinase 3 (FLT3) gene. Although both multi-targeted and FLT3 specific tyrosine kinase inhibitors (TKIs) are being utilized for clinical therapy, drug resistance, short remission periods, and high relapse rates are challenges that still need to be tackled. RNA interference (RNAi), mediated by short interfering RNA (siRNA), presents a mechanistically distinct therapeutic platform with the potential of personalization due to its gene sequence-driven mechanism of action. This study explored the use of a non-viral approach for delivery of FLT3 siRNA (siFLT3) in FLT3-ITD positive AML cell lines and primary cells as well as the feasibility of combining this treatment with drugs currently used in the clinic. Treatment of AML cell lines with FLT3 siRNA nanocomplexes resulted in prominent reduction in cell proliferation rates and induction of apoptosis. Quantitative analysis of relative mRNA transcript levels revealed downregulation of the FLT3 gene, which was accompanied by a similar decline in FLT3 protein levels. Moreover, an impact on leukemic stem cells was observed in a small pool of primary AML samples through significantly reduced colony numbers. An absence of a molecular response post-treatment with lipopolymer/siFLT3 complexes in peripheral blood mononuclear cells, obtained from healthy individuals, denoted a passive selectivity of the complexes towards malignant cells. The effect of combining lipopolymer/siFLT3 complexes with daunorubucin and FLT3 targeting TKI gilteritinib led to a significant augmentation of anti-leukemic activity. These findings demonstrate the promising potential of RNAi implemented with lipopolymer complexes for AML molecular therapy. The study prospectively supports the addition of RNAi therapy to current treatment modalities available to target the heterogeneity prevalent in AML. STATEMENT OF SIGNIFICANCE: We show that a clinically validated target, the FLT3 gene, can be eradicated in leukemia cells using non-viral RNAi. We validated these lipopolymers as effective vehicles to deliver nucleic acids to leukemic cells. The potency of the lipopolymers was superior to that of the 'gold-standard' delivery agent, lipid nanoparticles (LNPs), which are not effective in leukemia cells at clinically relevant doses. Mechanistic studies were undertaken to probe structure-function relationships for effective biomaterial formulations. Cellular and molecular responses to siRNA treatment have been characterized in cell models, including leukemia patient-derived cells. The use of the siRNA therapy with clinically used chemotherapy was demonstrated.