查看更多>>摘要：? 2022 Acta Materialia Inc.Moderate muscular injuries that exceed muscular tissue's auto-healing capacity are still a topic of noteworthy concern. Tissue engineering appeared as a promising therapeutic strategy capable of overcoming this unmet clinical need. To attain such goal, herein we propose an in situ-crosslinking gellan gum (GG)-based hydrogel tethered with a skeletal muscle-inspired laminin-derived peptide RKRLQVQLSIRTC(Q) and encapsulated with skeletal muscle cells (SMCs). Pre-hydrogel solutions presented decreasing shear viscosity with increasing shear rate and shear stress, and required low forces for extrusion, validating their injectability. The GGDVS hydrogel was functionalized with Q-peptide with 30% of efficiency. C2C12 were able to adhere to the developed hydrogel, remained living and spreading 7 days post-encapsulation. Q-peptide release studies indicated that 25% of the unbound peptide can be released from the hydrogels up to 7 days, dependent on the hydrogel formulation. Treatment of a chemically-induced muscular lesion in mice with an injection of C2C12-laden hydrogels improved myogenesis, primarily promoted by the C2C12. In accordance, a high density of myoblasts (α-SA+ and MYH7+) were localized in tissues treated with the C2C12 (alone or encapsulated in the hydrogel). α-SA protein levels were significantly increased 8 weeks post-treatment with C2C12-laden hydrogels and MHC protein levels were increased in all experimental groups 4 weeks post-treatment, in relation to the SHAM. Neovascularization and neoinnervation was also detected in the defects. Altogether, this study indicates that C2C12-laden hydrogels hold great potential for skeletal muscle regeneration. Statement of significance: We developed an injectable gellan gum-based hydrogel for delivering C2C12 into localized myopathic model. The gellan gum was biofunctinalized with laminin-derived peptide to mimic the native muscular ECM. In addition, hydrogel was physically tuned to mimic the mechanical properties of native tissue. To the best of our knowledge, this formula was used for the first time under the context of skeletal muscle tissue regeneration. The injectability of the developed hydrogel provided non-invasive administration method, combined with a reliable microenvironment that can host C2C12 with nominal inflammation, indicated by the survival and adhesion of encapsulated cells post-injection. The treatment of skeletal muscle defect with the cell-laden hydrogel approach significantly enhanced the regeneration of localized muscular trauma.
查看更多>>摘要：? 2022 Acta Materialia Inc.Vascularization of the poorly vascularized limbs affected by critical limb ischemia (CLI) is necessary to salvage the limbs and avoid amputation. Effective vascularization requires forming not only capillaries, but also arterioles and vessel branching. These processes rely on the survival, migration and morphogenesis of endothelial cells in the ischemic limbs. Yet endothelial cell functions are impaired by the upregulated TGFβ. Herein, we developed an injectable hydrogel-based drug release system capable of delivering both VEGF and Dll4 to synergistically restore endothelial cellular functions, leading to accelerated formation of capillaries, arterioles and vessel branching. In vitro, the Dll4 and VEGF synergistically promoted the human arterial endothelial cell (HAEC) survival, migration, and formation of filopodial structure, lumens, and branches under the elevated TGFβ1 condition mimicking that of the ischemic limbs. The synergistic effect was resulted from activating VEGFR2, Notch-1 and Erk1/2 signaling pathways. After delivering the Dll4 and VEGF via an injectable and thermosensitive hydrogel to the ischemic mouse hindlimbs, 95% of blood perfusion was restored at day 14, significantly higher than delivery of Dll4 or VEGF only. The released Dll4 and VEGF significantly increased density of capillaries and arterioles, vessel branching point density, and proliferating cell density. Besides, the delivery of Dll4 and VEGF stimulated skeletal muscle regeneration and improved muscle function. Overall, the developed hydrogel-based Dll4 and VEGF delivery system promoted ischemic limb vascularization and muscle regeneration. Statement of significance: Effective vascularization of the poorly vascularized limbs affected by critical limb ischemia (CLI) requires forming not only capillaries, but also arterioles and vessel branching. These processes rely on the survival, migration and morphogenesis of endothelial cells. Yet endothelial cell functions are impaired by the upregulated TGFβ in the ischemic limbs. Herein, we developed an injectable hydrogel-based drug release system capable of delivering both VEGF and Dll4 to synergistically restore endothelial cell functions, leading to accelerated formation of capillaries, arterioles and vessel branching.
查看更多>>摘要：? 2022 Acta Materialia Inc.Objective: Urogynecology meshes, typically manufactured from polypropylene, are widely used in the surgical treatment of stress urinary incontinence and pelvic organ prolapse. However, mesh-associated complications such as mesh exposure can develop in women undergoing mesh implantation, for which diabetes is an independent risk factor. We aimed to define the impact of diabetes on the vaginal immune response to mesh by comparing diabetic vs. normoglycemic conditions longitudinally in a rat sacrocolpopexy model. Methods: Diabetes (blood glucose ≥ 300 mg/dL) was induced in middle-aged female Wistar rats with streptozotocin (STZ). A polypropylene mesh was implanted on the vagina via modified sacrocolpopexy following bilateral ovariectomy and supracervical hysterectomy for 3-, 7-, and 42-days. Sham-operated controls underwent the same procedures without mesh. Mesh-associated inflammation, immune cell populations and cytokine/chemokine profiles were examined in the excised vaginal tissues. Results: Diabetes was reliably induced starting on the 3rd day following STZ injection. Under both normoglycemic and diabetic conditions, mesh caused a prolonged inflammatory response in the vagina with increased proinflammatory chemokines MCP-1 and MIP-1α as compared to Sham. Major differences between the two conditions were found at the later stage (42 days post-surgery), including an increased inflammation with larger foreign body granuloma and more giant cells at the mesh-tissue interface, increased fraction of macrophages in the immune cell population, and higher proinflammatory chemokine IP-10 in the diabetic group. Conclusion: Polypropylene mesh implanted on the vagina induces prolonged inflammation at the mesh-tissue interface. Diabetes increases the mesh-associated inflammation in the long term, which is related to a dysregulated macrophage response. Statement of significance: This study investigated the mechanism underlying the increased risk in women with diabetes for developing mesh complications such as mesh exposure. The significance includes: (1) it is the first study investigating vaginal host response to a prosthesis under the influence of diabetes; (2) the longitudinal study design elucidated the dynamic changes of vaginal immune response to mesh from very early to late stages; (3) our findings may inform future mechanistic studies and studies investigating preventive/therapeutic strategies to improve the outcomes of women with diabetes receiving vaginal implants.
查看更多>>摘要：? 2022In this study, we developed an enzyme- and pH-responsive dendronized poly(oligo-(ethylene glycol) methacrylate) (pOEGMA)-doxorubicin (DOX) polymeric prodrug, which combined the pOEGMA structure with a degradable peptide dendron. The introduction of the dendron in the prodrug hindered the entanglement of brush oligo-(ethylene glycol) (OEG) chains, allowed the prodrug to possess dual stimuli-responsiveness, and mediated self-assembly of the polymeric prodrug to form stable nanoparticles (NPs). Brush conformation of polyethylene glycol (PEG) side chains endowed the NPs with long-term circulation with a half-life of 16.0 h. The dual-responsive dendritic structure enhanced cellular uptake of NPs and facilitated drug release in response to overexpressed cathepsin B and an acidic pH in the tumor microenvironment, resulting in an enhanced therapeutic effect with a tumor inhibition rate of 72.9% for 4T1 tumor-bearing mice. The NPs were demonstrated to possess great hemocompatibility and biosafety. Therefore, this strategy could provide great insight for the design of poly(oligo-(ethylene glycol) methacrylate)-based copolymers as drug delivery carriers. Statement of significance: We propose a dual-stimuli-responsive dendronized strategy for improving the cancer therapeutic effect of the poly(oligo-(ethylene glycol) methacrylate) (pOEGMA)-based drug conjugates. The introduction of the functional dendron promotes self-assembly of the polymeric prodrug into nanoparticles, hindering the entanglement of brush oligo-(ethylene glycol) (OEG) chains in the conjugated drugs. The obtained poly OEGMA-GFLG-Dendron-NH-N=DOX nanoparticles maintains long circulation, while addresses the drug release issue due to the presence of high-density PEG. The drug delivery system exhibits a high therapeutic potentcy with negligible side effects.
查看更多>>摘要：? 2022Nearly all autologous tissue techniques and engineered tissue substitutes utilized for nipple reconstruction are hindered by scar contracture and loss of projection of the reconstructed nipple. The use of unprocessed costal cartilage (CC) as an internal support for the reconstructed nipple has not been widely adopted because of the excessively firm resultant construct. Herein we use a 3D-printed Poly-4-Hydroxybutyrate (P4HB) bioabsorbable scaffold filled with mechanically processed patient-derived CC to foster ingrowth of tissue in vivo to protect the regenerated tissue from contractile forces as it matures. After 6 months in vivo, newly formed spongy fibrovascular cartilaginous tissue was noted in processed CC filled 3D-printed scaffolds, which maintained significantly greater projection than reconstructions without scaffolds. Interestingly, 3D-printed P4HB scaffolds designed with an internal 3D lattice of P4HB filaments (without CC) displayed the fastest material absorption and vascularized adipose-fibrous tissue as demonstrated by SEM and histological analysis, respectively. Using 3D-printed P4HB scaffolds filled with either processed CC, a 3D P4HB lattice or no fills, we have engineered neo-nipples that maintain projection over time, while approximating the biomechanical properties of the native human nipple. We believe that this innovative 3D-printed P4HB nipple reconstruction scaffold will be readily translatable to the clinic. Statement of significance: Nearly all autologous tissue techniques and engineered tissue substitutes utilized for nipple reconstruction are hindered by scar contracture and substantial loss of projection of the reconstructed nipple, leading to significant patient dissatisfaction. Using 3D-printed P4HB scaffolds filled with either processed costal cartilage or 3D P4HB lattices, we have engineered neo-nipples that resist the forces induced by scar contracture, resulting in maintenance of neo-nipple projection over time and biomechanically approximating human nipples after 6 months in vivo implantation. This novel 3D-printed bioabsorbable P4HB scaffold will be readily translatable to the clinic to reconstruct nipples with patient-specific dimensions and long-lasting projection.
查看更多>>摘要：? 2022Neutrophils serve as a key contributor to the pathophysiology of myocardial ischemia reperfusion injury (MIRI), because the unregulated activation and infiltration of neutrophils lead to overwhelming inflammation in the myocardium to cause tissue damage. Herein, endothelial cell-targeting and reactive oxygen species (ROS)-ultrasensitive nanocomplexes (NCs) were developed to mediate efficient co-delivery of VCAM-1 siRNA (siVCAM-1) and dexamethasone (DXM), which cooperatively inhibited neutrophil recruitment by impeding neutrophil migration and adhesion. RPPT was first synthesized via crosslinking of PEI 600 with ditellurium followed by modification with PEG and the endothelial cell-targeting peptide cRGD. RPPT was allowed to envelope the DXM-loaded PLGA nanoparticles and condense the siVCAM-1. After systemic administration in rats experiencing MIRI, the cRGD-modified NCs efficiently targeted and entered the inflamed endothelial cells, wherein RPPT was sensitively degraded by over-produced ROS to trigger intracellular siVCAM-1 release and potentiate the VCAM-1 silencing efficiency. As a consequence of the complementary function of DXM and siVCAM-1, the NCs notably mitigated neutrophil infiltration into ischemic myocardium, provoking potent anti-inflammatory efficacy to reduce MIRI and recover cardiac function. The present study offers an effective approach for the controlled co-delivery of siRNA and drug cargoes, and it also highlights the importance of multi-dimensional manipulation of neutrophils in anti-inflammatory treatment. Statement of significance: The unregulated activation and infiltration of neutrophils lead to overwhelming inflammation in the myocardium after myocardial ischemia reperfusion injury (MIRI). Here, endothelial cell-targeting and ROS-ultrasensitive nanocomplexes (NCs), comprised of PLGA NPs decorated with cRGD-poly(ethylene glycol) (PEG)-modified, ditellurium-crosslinked PEI (RPPT), were developed to mediate efficient co-delivery of VCAM-1 siRNA (siVCAM-1) and dexamethasone (DXM). DXM and siVCAM-1 with complementary functions inhibited both the migration and adhesion of neutrophils, efficiently interventing the neutrophil recruitment and interrupting the self-amplified inflammation cascade in the injured myocardium. The molecular design of RPPT renders an effective example for constructing polymeric materials with high ROS sensitivity, and it resolves the critical dilemma related to polycation-mediated siRNA delivery, such as siRNA encapsulation versus release, and transfection efficiency versus toxicity.
查看更多>>摘要：? 2022 The Author(s)Atherosclerosis progression is a result of chronic and non-resolving inflammation, effective treatments for which still remain to be developed. We designed and developed branched poly(?-amino ester) nanoparticles (NPs) containing plasmid DNA encoding IL-10, a potent anti-inflammatory cytokine to atherosclerosis. The NPs (NP-VHPK) are functionalized with a targeting peptide (VHPK) specific for VCAM-1, which is overexpressed by endothelial cells at sites of atherosclerotic plaque. The anionic coating affords NP-VHPK with significantly lower toxicity than uncoated NPs in both endothelial cells and red blood cells (RBCs). Following injection of NP-VHPK in ApoE?/? mice, Cy5-labelled IL-10 significantly accumulates in both whole aortas and aortic sinus sections containing plaque compared to injection with a non-targeted control. Furthermore, IL-10 gene delivery results in an attenuation of inflammation locally at the plaque site. NP-VHPK may thus have the potential to reduce the inflammatory component of atherosclerosis in a safe and effective manner. Statement of significance: Atherosclerosis is a chronic inflammatory disease that results in the formation of lipid-laden plaques within vascular walls. Although treatments using drugs and antibodies are now beginning to address the inflammation in atherosclerosis, neither is sufficient for long-term therapy. In this paper, we introduce a strategy to deliver genes encoding the anti-inflammatory protein interleukin-10 (IL-10) in vivo. We showed that Branched Poly(?-aminoester) carrying the IL-10 gene are able to localize specifically at the plaque via surface-functionalized targeting moieties against inflamed VCAM-1 and/or ICAM-1 and to facilitate gene transcription by ECs to increase the local concentration of the IL-10 within the plaque. To date, there is no report involving non-viral nanotechnology to provide gene-based therapies for atherosclerosis.
查看更多>>摘要：? 2022 Acta Materialia Inc.Stimuli-responsive nanoplatforms for efficient delivery of drugs in an on-demand manner show promising potential for killing cancer cells with high accuracy and minimal invasiveness. Herein, taking advantage of the good tissue-penetrating depth of sonodynamic therapy (SDT), reactive oxygen species (ROS)-responsive nanoscale coordination polymers (NCPs) were designed through self-assembly of porphyrins (PP) and platinum, which contained ROS-cleavable thioketal (TK) linkers to enhance the release of doxorubicin (Dox) during SDT. Upon exposure to the ultrasound (US), the Dox-loaded NCPs (PTK@PEG/Dox) could generate high amounts of cytotoxic ROS and heat, which not only induced the apoptosis of MCF-7 cells but also facilitated the efficient release of Dox due to the decomposition of the ROS-sensitive TK linkers, achieving the synergistic therapy of US-induced therapy and chemotherapy. After being modified with Arg-Gly-Asp (RGD) peptide, RGD/PTK@PEG exhibited a good targeting ability to cancer cells. Importantly, using the multicellular tumor spheroids (MCTS) derived from MCF-7 cells as a model, the RGD/PTK@PEG/Dox exhibited an efficient and controlled release behavior of Dox under the US irradiation, accompanying a tremendous anti-cancer effect for inducing apoptosis in the solid tumor tissues. This work provided a potential strategy to design controllable and stimuli-responsive nanoplatforms for synergistic/enhanced US-induced cancer therapy. Statement of significance: Stimulus-responsive nanoplatforms can deliver drugs efficiently in an on-demand manner, showing the potential to kill cancer cells with high accuracy and minimal invasiveness. Taking advantage of the good penetration ability of ultrasound (US), nanoscale coordination polymers (NCP) composed of porphyrin (PP), thioketal (TK) linkers, and platinum(II) were prepared via a coordination-driven self-assembly procedure. After doxorubicin (Dox) was loaded on the NCP (PTK@PEG/Dox), the nanoplatform responded to reactive oxygen species (ROS) under the stimulation of US, and induced the on-demand release of Dox, thereby achieving the combined therapeutic effect of sonodynamic therapy (SDT) and chemotherapy for cancer. This work provides a potential strategy for the development of controllable and stimuli-responsive nanoplatforms for enhanced ultrasound-induced cancer therapy.
查看更多>>摘要：? 2022 Elsevier LtdSupramolecular nanomedicine assembly combined with polypeptide prodrug could become a powerful strategy to minimize drug leakage in blood circulation and trigger sufficient drug release at tumor tissue. Here, we developed a charge-reversal amphiphilic pillar[5]arene-modified polypeptide (P5-PLL-DMA), and reactive oxygen species (ROS)-sensitive polypeptide prodrug (P-PLL-DOX) including a ROS-cleavable thioketal (TK) linker between doxorubicin (DOX) and poly(L-lysine) (PLL), which could assemble via pillar[5]arene host-guest recognition, and further encapsulate chlorin e6 (Ce6) to obtain a supramolecular polypeptide prodrug (SPP-DOX/Ce6). The chemical conjugation to load drugs of DOX and the negatively charge of SPP-DOX/Ce6 could prevent premature drug leakage, and reduce undesirable interaction with serum proteins to enhance stability under physiological conditions (pH 7.4). Simultaneously, the carried charge of SPP-DOX/Ce6 reversed from negative to positive could effectively enhance the cellular internalization for efficient DOX delivery under acidic tumor microenvironment (pH 6.5). Upon 660 nm near-infrared light (NIR) irradiation, the ROS generated by encapsulated Ce6 rapidly cleaved the TK linker to release activated DOX, inducing the tumor-specific drug delivery. This intelligent supramolecular polypeptide prodrug based on pillar[5]arene host-guest recognition represents new avenues to develop stimulus responsive prodrug for enhanced cancer therapy with minimized the side effect. Statement of significance: In this work, a pH/ROS dual-sensitive supramolecular polypeptide prodrug (SPP-DOX/Ce6) was developed to minimize drug leakage in blood circulation and trigger sufficient drug release at tumor tissue. The chemical conjugation to load drugs of DOX via a ROS-cleavable thioketal (TK) linker and the distinctive charge-reversal capacity of SPP-DOX/Ce6 significantly enhances the stability under physiological conditions (pH 7.4), while facilitates cellular uptake at tumor site (pH 6.8). Upon 660 nm near-infrared light (NIR) irradiation, the ROS generated by encapsulated Ce6 induces the rapid cleavage of TK linker to release activated DOX, achieving a tumor-specific drug delivery. This intelligent supramolecular polypeptide prodrug SPP-DOX/Ce6 provides an effective strategy to construct stimulus responsive prodrug for enhanced cancer therapy.
查看更多>>摘要：? 2022Traditional anticancer treatments directly target tumor cells. In contrast, cancer immunotherapy fortifies host immunity. Nanoparticles that incorporate both immunomodulatory and chemotherapeutic agents regulate the tumor microenvironment by activating immune cells and enhancing antitumor immunity. Nanoparticle-based cancer immunotherapy has received considerable attention and has been extensively studied in recent years. In this study, we developed a targeted drug delivery system to enhance immunotherapeutic efficacy and overcome drug resistance by inducing tumor apoptosis and immunogenic cell death (ICD), and activating immune cells. Periodic mesoporous organosilica nanoparticles (PMOs) bore tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on their surfaces, and their inner cores were loaded with doxorubicin (DOX). TRAIL enhanced the nanoparticle-targeting capacity and worked synergistically with DOX against breast cancer cells in vitro and in vivo. Furthermore, we revealed for the first time the ability of PMOs to activate dendritic cells (DCs) and elevate ICD levels of DOX in vitro, and TRAIL further enhances the immunomodulatory function of PMOs. Systemic exposure to DOX@PMO-hT induced an immune response, activated DCs and CD4+ and CD8+ T cells, and significantly suppressed tumor growth in a 4T1-bearing immunocompetent mouse model. Overall, our study demonstrates that TRAIL-modified, DOX-embedded PMO nanoparticles represent a good candidate for tumor-targeted immunotherapy, which has relatively superior therapeutic efficacy and highly promising future application prospects. Statement of significance: This study revealed for the first time the ability of PMOs to elevate ICD levels and activate DCs in vitro. The results explained the immunomodulatory function of PMOs and demonstrated the synergistic effects of TRAIL and DOX in triple-negative breast cancer. In addition, immunomodulatory effects of the drug delivery vectors constructed in this study were verified in vivo.
NSTL
Elsevier