Gelatin/heparin coated bio-inspired polyurethane composite fibers to construct small-caliber artificial blood vessel grafts.

Long-term patency and ability for revascularization remain challenges for small-caliber blood vessel grafts to treat cardiovascular diseases clinically. Here, a gelatin/heparin coated bio-inspired polyurethane composite fibers-based artificial blood vessel with continuous release of NO and biopeptides to regulate vascular tissue repair and maintain long-term patency is fabricated. A biodegradable polyurethane elastomer that can catalyze S-nitrosothiols in the blood to release NO is synthesized (NPU). Then, the NPU core-shell structured nanofiber grafts with requisite mechanical properties and biopeptide release for inflammation manipulation are fabricated by electrospinning and lyophilization. Finally, the surface of tubular NPU nanofiber grafts is coated with heparin/gelatin and crosslinked with glutaraldehyde to obtain small-caliber artificial blood vessels (ABVs) with the ability of vascular revascularization. We demonstrate that artificial blood vessel grafts promote the growth of endothelial cells but inhibit the growth of smooth muscle cells by the continuous release of NO; vascular grafts can regulate inflammatory balance for vascular tissue remodel without excessive collagen deposition through the release of biological peptides. Vascular grafts prevent thrombus and vascular stenosis to obtain long-term patency. Hence, our work paves a new way to develop small-caliber artificial blood vessel grafts that can maintain long-term patency in vivo and remodel vascular tissue successfully.

Perfluorocarbon Nanoparticles Incorporating Ginkgolide B: Artificial O2 Carriers with Antioxidant Activity and Antithrombotic Effect.

Ischemic stroke primarily leads to insufficient oxygen delivery in ischemic area. Prompt reperfusion treatment for restoration of oxygen is clinically suggested but mediates more surging reactive oxygen species (ROS) generation and oxidative damage, known as ischemia-reperfusion injury (IRI). Therefore, the regulation of oxygen content is a critical point to prevent cerebral ischemia induced pathological responses and simultaneously alleviate IRI triggered by the sudden oxygen restoration. In this work, we constructed a perfluorocarbon (PFC)-based artificial oxygen nanocarrier (PFTBA-L@GB), using an ultrasound-assisted emulsification method, alleviates the intracerebral hypoxic state in ischemia stage and IRI after reperfusion. The high oxygen solubility of PFC allows high oxygen efficacy. Furthermore, PFC has the adhesion affinity to platelets and prevents the overactivation of platelet. The encapsulated payload, ginkgolide B (GB) exerts its anti-thrombosis by antagonism on platelet activating factor and antioxidant effect by upregulation of antioxidant molecular pathway. The versatility of the present strategy provides a practical approach to build a simple, safe, and relatively effective oxygen delivery agent to alleviate hypoxia, promote intracerebral oxygenation, anti-inflammatory, reduce intracerebral oxidative stress damage and thrombosis and caused by stroke.

Phenylboronic Ester-Bridged Chitosan/Myricetin Nanomicelle for Penetrating the Endothelial Barrier and Regulating Macrophage Polarization and Inflammation against Ischemic Diseases.

The brain and liver are more susceptible to ischemia and reperfusion (IR) injury (IRI), which triggers the reactive oxygen species (ROS) burst and inflammatory cascade and results in severe neuronal damage or hepatic injury. Moreover, the damaged endothelial barrier contributes to proinflammatory activity and limits the delivery of therapeutic agents such as some macromolecules and nanomedicine despite the integrity being disrupted after IRI. Herein, we constructed a phenylboronic-decorated chitosan-based nanoplatform to deliver myricetin, a multifunctional polyphenol molecule for the treatment of cerebral and hepatic ischemia. The chitosan-based nanostructures are widely studied cationic carriers for endothelium penetration such as the blood-brain barrier (BBB) and sinusoidal endothelial barrier (SEB). The phenylboronic ester was chosen as the ROS-responsive bridging segment for conjugation and selective release of myricetin molecules, which meanwhile scavenged the overexpressed ROS in the inflammatory environment. The released myricetin molecules fulfill a variety of roles including antioxidation through multiple phenolic hydroxyl groups, inhibition of the inflammatory cascade by regulation of the macrophage polarization from M1 to M2, and endothelial injury repairment. Taken together, our present study provides valuable insight into the development of efficient antioxidant and anti-inflammatory platforms for potential application against ischemic disease.

Bioinspired Platelet-Anchored Electrospun Meshes for Tight Inflammation Manipulation and Chronic Diabetic Wound Healing.

Tight manipulation of the initial leukocytes infiltration and macrophages plasticity toward the M2 phenotype remain a challenge for diabetic wound healing. Inspired by the platelet function and platelet-macrophage interaction, a platelet-anchored polylactic acid-b-polyethylene glycol-b-polylactic acid (PLA-PEG-PLA) electrospun dressing is developed for inflammatory modulation and diabetic wounds healing acceleration. PLA-PEG-PLA electrospun meshes encapsulated with thymosin ß4 (Tß4) and CaCl2 is fabricated with electrospinning, followed by immersion of electrospun mesh in platelet-rich plasma to firmly anchor the platelets. It is demonstrated that the anchored platelets on electrospun mesh can enhance the initial macrophage recruitment and control the Tß4 release from electrospun meshes to facilitate the macrophages polarization to the M2 phenotype. The inflammatory regulation promotes the expression of vascular endothelial growth factor and the migration of vascular endothelial cells for angiogenesis, resulting in accelerated diabetic wounds healing. Therefore, this work paved a new way to design platelet-inspired electrospun meshes for inflammation manipulation and diabetic wound healing.

Silane-Functionalized Metal-Organic Frameworks for Stimuli-Responsive Drug Delivery Systems: A New Universal Strategy.

A new universal strategy for silane functionalization of metal-organic frameworks (MOFs) was developed. It was demonstrated that silanes were coupled both with terminal hydroxyl (OH) groups and with bridging OH groups of metal-oxo clusters of MOFs through condensation reactions between the silanols of hydrolyzed silanes and the terminal/bridging OH groups to form metal-O-Si bonds. A wide variety of functionalization of MOFs with conventional silanes can be realized by combining synthesis reactions in the solution phase and chemical modifications on the surface. Multivalent supramolecular nanovalves based on the host-guest chemistry of cyclodextrin polymer (CDP) and benzimidazole stalks silanized on the nanoscale MOF (NMOF) surface were successfully constructed. The CDP-valved NMOFs showed the excellent performance of low pH- and α-amylase-responsive controlled drug release. In vitro and in vivo results demonstrated that the CDP-valved NMOFs had a significant inhibitory effect on tumor growth and almost no damage/toxicity to normal tissues. The silanization strategy is universal and opens up a new way for the functionalization of MOFs, which are endowed with a wide variety of applications spanning gas storage, chemical sensing, adsorption and separation, heterogeneous catalysis, and drug delivery.

Bioactive fibrous scaffolds with programmable release of polypeptides regulate inflammation and extracellular matrix remodeling.

Inflammation manipulation and extracellular matrix (ECM) remodeling for healthy tissue regeneration are critical requirements for tissue engineering scaffolds. To this end, the bioactive polycaprolactone (PCL)-based scaffolds are fabricated to release aprotinin and thymosin ß4 (Tß4) in a programmable manner. The core part of the fiber is composed of hyaluronic acid and Tß4, and the shell is PCL, which is further coated with heparin/gelatin/aprotinin to enhance biocompatibility. The in vitro assay demonstrates that the controlled release of aprotinin prevents initial excessive inflammation. The subsequent release of Tß4 after 3 days induces the transition of macrophages from M1 into M2 polarization. The manipulation of inflammatory response further controls the expression of transforming growth factor-ß and fibroblast activation, which oversee the quantity and quality of ECM remodeling. In addition, the gradual degradation of the scaffold allows cells to proliferate within the platform. In vivo implant evaluation convinces that PCL-based scaffolds possess the high capability to control the inflammatory response and restore the ECM to normal conditions. Hence, our work paves a new way to develop tissue engineering scaffolds for inflammation manipulation and ECM remodeling with peptide-mediated reactions.

Chlorogenic Acid-Conjugated Nanoparticles Suppression of Platelet Activation and Disruption to Tumor Vascular Barriers for Enhancing Drug Penetration in Tumor.

Hypercoagulation threatens the lives of cancer patients and cancer progression. Platelet overactivation attributes to the tumor-associated hypercoagulation and maintenance of the tumor endothelial integrity, leading to limited intratumoral perfusion of nanoagents into solid tumors in spite of the enhanced penetration and retention effect (EPR). Therefore, the clinical application of nanotherapeutics in solid cancer still faces great challenges. Herein, this work establishes platelet inhibiting nanoagents based on FeIII -doped C3 N4 coloaded with the chemotherapy drug and the antiplatelet drug chlorogenic acid (CA), further opening tumor vascular endothelial junctions, thereby disrupting the tumor vascular endothelial integrity, and enhancing drug perfusion. Moreover, CA not only damages the cancer cells but also potentiates the cytotoxicity induced by the chemotherapy drug doxorubicin, synergistically ablating the tumor tissue. Further, the introduction of CA relieves the original causes of the hypercoagulable state such as tissue factor (TF), thrombin, and matrix metalloproteinases (MMPs) secreted by cancer cells. It is anticipated that the hypercoagulation- and platelet-inhibition strategy by integration of phenolic acid CA into chemotherapy provides insights into platelet inhibition-assisted theranostics based on nanomedicines.

Controlled release of nitric oxide for enhanced tumor drug delivery and reduction of thrombosis risk.

Platelets activation and hypercoagulation induced by tumor cell-specific thrombotic secretions such as tissue factor (TF) and cancer procoagulant (CP), microparticles (MPs), and cytokines not only increase cancer-associated thrombosis but also accelerate cancer progress. In addition, the tumor heterogeneity such avascular areas, vascular occlusion and interstitial fluid pressure still challenges efficient drug delivery into tumor tissue. To overcome these adversities, we herein present an antiplatelet strategy based on a proteinic nanoparticles co-assembly of l-arginine (LA) and photosensitizer IR783 for local NO release to inhibit the activation of tumor-associated platelets and normalize angiogenesis, suppressing thrombosis and increasing tumoral accumulation of the nanoagent. In addition, NIR-controlled release localizes the NO spatiotemporally to tumor-associated platelets and prevents undesirable systemic bleeding substantially. Moreover, NO can transform to more cytotoxic peroxynitrite to destroy cancer cells. Our study describes an antiplatelet-directed cancer treatment, which represents a promising area of targeted cancer therapy.

Thrombus Inhibition and Neuroprotection for Ischemic Stroke Treatment through Platelet Regulation and ROS Scavenging.

Ischemic stroke is caused by cerebrovascular stenosis or occlusion. Excessive reactive oxygen species (ROS) are the focus-triggering factor of irreversible injury in ischemic regions, which result in harmful cascading effects to brain tissue, such as inflammation and microthrombus formation. In the present work, we designed nanodelivery systems (NDSs) based on MnO2 loaded with Ginkgolide B (GB) for restoring the intracerebral microenvironment in ischemic stroke, such as ROS scavenging, O2 elevation, thrombus inhibition and damage repair. GB can activate the endogenous antioxidant defense of cells by enhancing the nuclear factor-E2-related factor 2 (Nrf2) signalling pathway, thus protecting brain tissue from oxidative damage. However, the blood-brain barrier (BBB) is also a therapeutic obstacle for the delivery of these agents to ischemic regions. MnO2 nanoparticles have an inherent BBB penetration effect, which enhances the delivery of therapeutic agents within brain tissue. MnO2 , with mimicking enzymatic activity, can catalyze the decomposition of overproduced H2 O2 in the ischemic microenvironment to O2 , meanwhile releasing platelet-antagonizing GB molecules, thus alleviating cerebral hypoxia, oxidative stress damage, and microthrombus generation. This study may provide a promising therapeutic route for regulating the microenvironment of ischemic stroke through a combined function of ROS scavenging, microthrombus inhibition, and BBB penetration.

Bioactive engineered scaffolds based on PCL-PEG-PCL and tumor cell-derived exosomes to minimize the foreign body reaction.

Long-term presence of M1 macrophages causes serious foreign body reaction (FBR), which is the main reason for the failure of biological scaffold integration. Inducing M2 polarization of macrophages near scaffolds to reduce foreign body response has been widely researched. In this work, inspired by the special capability of tumor exosomes in macrophages M2 polarization, we integrate tumor-derived exosomes into biological scaffolds to minimize the FBR. In brief, breast cancer cell-derived exosomes are loaded into polycaprolactone-b-polyethylene glycol-b-polycaprolactone (PCL-PEG-PCL) fiber scaffold through physical adsorption and entrapment to constructed bioactive engineered scaffold. In cellular experiments, we demonstrate bioactive engineered scaffold based on PCL-PEG-PCL and exosomes can promote the transformation of macrophages from M1 to M2 through the PI3K/Akt signaling pathway. In addition, the exosomes release gradually from scaffolds and act on the macrophages around the scaffolds to reduce FBR in a subcutaneous implant mouse model. Compared with PCL-PEG-PCL scaffolds without exosomes, bioactive engineered scaffolds reduce significantly inflammation and fibrosis of tissues around the scaffolds. Therefore, cancer cell-derived exosomes show the potential for constructing engineered scaffolds in inhibiting the excessive inflammation and facilitating tissue formation.

A dynamic remodeling bio-mimic extracellular matrix to reduce thrombotic and inflammatory complications of vascular implants.

Thrombotic and inflammatory complications induced by vascular implants remain a challenge to treat cardiovascular disease due to the lack of self-adaption and functional integrity of implants. Inspired by the dynamic remodeling of the extracellular matrix (ECM), we constructed a bio-mimic ECM with a dual-layer nano-architecture on the implant surface to render the surface adaptive to inflammatory stimuli and remodelable possessing long-term anti-inflammatory and anti-thrombotic capability. The inner layer consists of PCL-PEG-PCL [triblock copolymer of polyethylene glycol and poly(ε-caprolactone)]/Au-heparin electrospun fibers encapsulated with indomethacin while the outer layer is composed of polyvinyl alcohol (PVA) and ROS-responsive poly(2-(4-((2,6-dimethoxy-4-methylphenoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (PBA) fibers. In response to acute inflammation after vascular injury, the outer layer reduces ROS rapidly by PBA degradation for inflammation suppression. The degraded outer layer facilitates inner layer reconstruction with enhanced hemocompatibility through the H-bond between PVA and PCL-PEG-PCL. Furthermore, chronic inflammation is effectively depressed with the sustained release of indomethacin from the inner layer. The substantial enhancement of the functional integrity of implants and reduction of thrombotic and inflammatory complications with the self-adaptive ECM are demonstrated both in vitro and in vivo. Our work paves a new way to develop long-term anti-thrombotic and anti-inflammatory implants with self-adaption and self-regulation properties.

Biomimetic nano-NOS mediated local NO release for inhibiting cancer-associated platelet activation and disrupting tumor vascular barriers.

Platelets attribute to the hypercoagulation of blood and maintenance of the tumor vascular integrity, resulting in limited intratumoral perfusion of nanoparticle into solid tumors. To overcome these adversities, we herein present an antiplatelet strategy based on erythrocyte membrane-enveloped proteinic nanoparticles that biomimic nitric oxide synthase (NOS)with co-loading of l-Arginine (LA) and photosensitizer IR783 for local NO release and inhibition of the activation of tumor-associated platelets specifically, thereby enhancing vascular permeability and accumulation of the nanoparticles in tumors. A cRGD-immobolized membrane structure is constructed to actively target platelets and cancer cells respectively, through overexpressed integrin receptors such as integrin αIIbß3 and αvß3, accelerating the inhibition of platelet activation and endocytosis of nanoparticles by tumor cells. Bio-mimicking the arginine/NO pathway in vivo, synergistical delivery of LA and IR783 enables LA molecules readily oxidize to NO with O2 that is mediated by activated IR783, the resulted NO not only retards the activity of platelets to disrupt the vascular integrity of tumor but also enhances toxicity to cancer cells. In addition, NIR-controlled release localizes the NO spatiotemporally to tumor-associated platelets and prevents undesirable systemic bleeding substantially. The reduction of the hypercoagulable state is further demonstrated by the down-regulation of tissues factor (TF) expression in tumor cells. Our study describes a promising approach to combat cancer, which advances the biomimetic NOS system as the potent therapeutic forces toward clinic applications.

Thermal and Reactive Oxygen Species Dual-Responsive OEGylated Polysulfides with Oxidation-Tunable Lower Critical Solution Temperatures.

In this work, two monomethoxy oligo(ethylene glycol) (OEG)-substituted episulfides are prepared and a series of polysulfides are synthesized with subsequent ring-opening polymerization. The OEGylated polysulfides exhibit thermal and reactive oxygen species (ROS) dual-responsive behavior. Their lower critical solution temperatures (LCSTs) are close to human body temperature and depend on the degree of polymerization and OEG length. Notably, the LCST of the polysulfide increases linearly with the oxidation degree by H2 O2 , showing a highly tunable change regulated by the ratio between hydrophobic sulfide and hydrophilic sulfoxide/sulfone in the backbone. Further, the OEGylated polysulfide can act as a ROS scavenger to protect red blood cells (RBCs) from oxidative damage in an RBCs aging model in vitro. This work paves a facile way to synthesize LCST-tunable polysulfides, which hold great promise in biological applications.

Hydrogen Peroxide and Glutathione Dual Redox-Responsive Nanoparticles for Controlled DOX Release.

Polymer nanoparticulate drug delivery systems that respond to reactive oxygen species (ROS) and glutathione (GSH) simultaneously at biologically relevant levels hold great promise to improve the therapeutic efficacy to cancer cells with reduced side effects of chemo drugs. Herein, a novel redox dual-responsive amphiphilic block copolymer (ABP) that consists of a hydrophilic poly (ethylene oxide) block and a hydrophobic block bearing disulfide linked phenylboronic ester group as pendant is synthesized, and the DOX loaded nanoparticles (BSN-DOX) based on ABPs with varied hydrophobic block length are fabricated for DOX delivery. The self-immolative leaving reaction of phenylboronic ester triggered by extracellular ROS and the cleavage of disulfide linkages induced by intracellular GSH both lead to rapid DOX release from BSN-DOX, resulting in an on-demand DOX release. Moreover, BSN-DOX show better tumor inhibition and lower side effects in vivo compared with free drug.

Inhibition of Inflammation-Associated Thrombosis with ROS-Responsive Heparin-DOCA/PVAX Nanoparticles.

Inflammation-associated thrombosis is a non-negligible source of mortalities and morbidities worldwide. To manipulate inflammation-associated coagulation, nanoparticles that contain anti-inflammatory polymer (copolyoxalate containing vanillyl alcohol, PVAX) and anti-thrombotic heparin derivative deoxycholic acid (Hep-DOCA) are prepared. The strategy takes advantage of the reducted side effects of heparin through heparin conjugation, achievement of long-term anti-inflammation by inflammation-trigged release of anti-inflammatory agents, and formation of PVAX/heparin-DOCA nanoparticles by co-self-assembly. It is demonstrated that the Hep-DOCA conjugate and PVAX are synthesized successfully; PVAX and Hep-DOCA nanodrugs (HDP) are obtained by co-assembly; the HDP nanoparticles effectively reduce the inflammation and coagulation without inducing lethal bleeding both in vivo and in vitro. The method provided here is versatile and effective, which paves new way to develop nanodrugs to treat inflammation-associated thrombosis safely.

Biomimicking Dual-Responsive Extracellular Matrix Restoring Extracellular Balance through the Na/K-ATPase Pathway.

Biomedical implant mimicking the physiological extracellular matrix (ECM) is a new strategy to modulate the cell microenvironment to improve implant integrity and longevity. However, the biomimicking ECM suffers from low sensitivity to pathological change and low efficiency to restore the physiological state in vivo. To overcome these problems, reactive oxygen species (ROS) and K+ dual-responsive micro-/nanofibers that encapsulate ascorbic acid-2-glucoside (AA-2G) are fabricated on an elastomer substrate with electrospinning to mimic the ECM. The strategy is based on the fact that ROS and K+ dual responsiveness enhance the sensitivity of the ECM to pathological changes and delivery of AA-2G from the ECM to cell membrane promotes reactivating Na/K-ATPase and shifting cellular diseased conditions to the normal state. We demonstrate that the ROS and K+-responsive tripolymer of poly(ethylene glycol)diacrylate, 1,2-ethanedithiol, and 4-nitrobenzo-18-crown-6-ether (PEGDA-EDT-BCAm) are synthesized successfully; the ECM composed of acylated poly(caprolactone)/PEGDA-EDT-BCAm/AA-2G micro-/nanofibers is prepared through reactive electrospinning; the ECM is sensitive to ROS and K+ concentration in the microenvironment to release AA-2G, which targets the membrane to remove the excessive ROS and reactivate Na/K-ATPase; as a result, the ECM reduces oxidative stress and restores the extracellular physiological state both in vitro and in vivo. This work provides basic principles to design an implant that can adjust the extracellular microenvironment while avoiding pathogenicity to improve implant integrity and longevity in vivo.

Construction of K+ responsive surface on SEBS to reduce the hemolysis of preserved erythrocytes.

Hemolysis of stored erythrocytes is a big obstacle for the development of new plasticizer-free polymer containers. Hemolysis is mainly caused by cell membrane oxidation and cation leaks from the intracellular fluid during storage. To construct an anti-hemolytic surface for a plasticizer-free polymer, we fabricated 2-O-α-d-glucopyranosyl-l-ascorbic acid (AA-2G)-loaded polycaprolactone (PCL)-crown ether micro/nanofibers on the surface of styrene-b-(ethylene-co-butylene)-b-styrene (SEBS). Our strategy is based on the sensitive response of the crown ether to leaked potassium, causing the release of AA-2G, the AA-2G can then remove the excess ROS, maintaining the Na/K-pump activity and the cell integrity. We demonstrated that the PCL-crown ether micro/nanofibers have been well prepared on the surface of SEBS; the micro/nanofibers provide a sensitive response to excess K+ and trigger the rapid release of AA-2G. AA-2G then acts as an antioxidant to reduce the excess ROS and maintain the Na/K-pump activity to mitigate cation leaks, resulting in the reduced hemolysis of the preserved erythrocytes. Our work thus provides a novel method for the development of plasticizer-free polymers for the storage of erythrocytes, and has the potential to be used to fabricate long-term anti-hemolytic biomaterials for in vivo use.