Tumor microenvironment responsive self-cascade catalysis for synergistic chemo/chemodynamic therapy by multifunctional biomimetic nanozymes.

Chemodynamic therapy (CDT) is an emerging approach to treat cancer based on the tumor microenvironment (TME), but its limited content of endogenous hydrogen peroxide (H2O2) weakens the anticancer effects. Herein, a multifunctional biomimetic nanozyme (Se@SiO2-Mn@Au/DOX, named as SSMA/DOX) is fabricated, which undergoes TME responsive self-cascade catalysis to facilitate MRI guided enhanced chemo/chemodynamic therapy. The SSMA/DOX nanocomposites (NCs) responsively degrade in acidic conditions of tumor to release Se, DOX, Au and Mn2+. Mn2+ not only enables MRI to guided therapy, but also catalyzes the endogenous H2O2 into hydroxyl radical (˙OH) for CDT. In addition, the Au NPs continuously catalyze glucose to generate H2O2, enhancing CDT by supplementing a sufficiently reactive material and cutting off the energy supply of the tumor by consuming glucose. Simultaneously, Se enhances the chemotherapy of doxorubicin hydrochloride (DOX) and CDT by upregulating ROS in the tumor cells, achieving remarkable inhibition effect towards tumor. Moreover, SSMA/DOX NCs have good biocompatibility and degradability, which avoid long-term toxicity and side effects. Overall, the degradable SSMA/DOX NCs provide an innovative strategy for tumor microenvironment responsive self-cascade catalysis to enhance tumor therapy.

Directed-evolution of translation system for efficient unnatural amino acids incorporation and generalizable synthetic auxotroph construction.

Site-specific incorporation of unnatural amino acids (UAAs) with similar incorporation efficiency to that of natural amino acids (NAAs) and low background activity is extremely valuable for efficient synthesis of proteins with diverse new chemical functions and design of various synthetic auxotrophs. However, such efficient translation systems remain largely unknown in the literature. Here, we describe engineered chimeric phenylalanine systems that dramatically increase the yield of proteins bearing UAAs, through systematic engineering of the aminoacyl-tRNA synthetase and its respective cognate tRNA. These engineered synthetase/tRNA pairs allow single-site and multi-site incorporation of UAAs with efficiencies similar to those of NAAs and high fidelity. In addition, using the evolved chimeric phenylalanine system, we construct a series of E. coli strains whose growth is strictly dependent on exogenously supplied of UAAs. We further show that synthetic auxotrophic cells can grow robustly in living mice when UAAs are supplemented.

Combination of Near-Infrared Photoimmunotherapy Using Trastuzumab and Small Protein Mimetic for HER2-Positive Breast Cancer.

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer therapy based on a monoclonal antibody conjugated to a photosensitizer (IR700Dye) that is activated by near-infrared light irradiation. We previously reported on the use of NIR-PIT with a small protein mimetic, the Affibody molecule (6-7 kDa), instead of a monoclonal antibody. In this study, we investigated a combination of NIR-PIT for HER2-positive breast cancer cells (SK-BR3, MDA-MB361, and JIMT1) with HER2 Affibody-IR700Dye conjugate and trastuzumab-IR700Dye conjugate. HER2 Affibody and trastuzumab target different epitopes of the HER2 protein and do not compete. In vitro, the combination of NIR-PIT using both HER2 Affibody-IR700Dye conjugate and trastuzumab-IR700Dye conjugate induced necrotic cell death of HER2-positive breast cancer cells without damage to HER2-negative breast cancer cells (MCF7). It was more efficient than NIR-PIT using either the HER2 Affibody-IR700Dye conjugate alone or the trastuzumab-IR700Dye conjugate alone. Additionally, this combination of NIR-PIT was significantly effective against HER2 low-expressing cancer cells, trastuzumab-resistant cells (JIMT1), and brain metastatic cells of breast cancer (MDA-MB361). Furthermore, in vivo imaging exhibited the strong fluorescence intensity of both HER2 Affibody-IR700Dye conjugates and trastuzumab-Alexa488 conjugates in HER2-positive tumor, indicating that both HER2 Affibody and trastuzumab specifically bind to HER2-positive tumors without competing with each other. In conclusion, the combination of NIR-PIT using both HER2 Affibody and trastuzumab expands the targeting scope of NIR-PIT for HER2-positive breast cancer.

Macrophage-biomimetic porous Se@SiO2 nanocomposites for dual modal immunotherapy against inflammatory osteolysis.

BACKGROUND: Inflammatory osteolysis, a major complication of total joint replacement surgery, can cause prosthesis failure and necessitate revision surgery. Macrophages are key effector immune cells in inflammatory responses, but excessive M1-polarization of dysfunctional macrophages leads to the secretion of proinflammatory cytokines and severe loss of bone tissue. Here, we report the development of macrophage-biomimetic porous SiO2-coated ultrasmall Se particles (porous Se@SiO2 nanospheres) to manage inflammatory osteolysis. RESULTS: Macrophage membrane-coated porous Se@SiO2 nanospheres(M-Se@SiO2) attenuated lipopolysaccharide (LPS)-induced inflammatory osteolysis via a dual-immunomodulatory effect. As macrophage membrane decoys, these nanoparticles reduced endotoxin levels and neutralized proinflammatory cytokines. Moreover, the release of Se could induce macrophage polarization toward the anti-inflammatory M2-phenotype. These effects were mediated via the inhibition of p65, p38, and extracellular signal-regulated kinase (ERK) signaling. Additionally, the immune environment created by M-Se@SiO2 reduced the inhibition of osteogenic differentiation caused by proinflammation cytokines, as confirmed through in vitro and in vivo experiments. CONCLUSION: Our findings suggest that M-Se@SiO2 have an immunomodulatory role in LPS-induced inflammation and bone remodeling, which demonstrates that M-Se@SiO2 are a promising engineered nanoplatform for the treatment of osteolysis occurring after arthroplasty.

Peroxidase Mimetic Nanozymes in Cancer Phototherapy: Progress and Perspectives.

Nanomaterial-mediated cancer therapeutics is a fast developing field and has been utilized in potential clinical applications. However, most effective therapies, such as photodynamic therapy (PDT) and radio therapy (RT), are strongly oxygen-dependent, which hinders their practical applications. Later on, several strategies were developed to overcome tumor hypoxia, such as oxygen carrier nanomaterials and oxygen generated nanomaterials. Among these, oxygen species generation on nanozymes, especially catalase (CAT) mimetic nanozymes, convert endogenous hydrogen peroxide (H2O2) to oxygen (O2) and peroxidase (POD) mimetic nanozymes converts endogenous H2O2 to water (H2O) and reactive oxygen species (ROS) in a hypoxic tumor microenvironment is a fascinating approach. The present review provides a detailed examination of past, present and future perspectives of POD mimetic nanozymes for effective oxygen-dependent cancer phototherapeutics.

Tuning Microbial Activity via Programmatic Alteration of Cell/Substrate Interfaces.

A wide portfolio of advanced programmable materials and structures has been developed for biological applications in the last two decades. Particularly, due to their unique properties, semiconducting materials have been utilized in areas of biocomputing, implantable electronics, and healthcare. As a new concept of such programmable material design, biointerfaces based on inorganic semiconducting materials as substrates introduce unconventional paths for bioinformatics and biosensing. In particular, understanding how the properties of a substrate can alter microbial biofilm behavior enables researchers to better characterize and thus create programmable biointerfaces with necessary characteristics on demand. Herein, the current status of advanced microorganism-inorganic biointerfaces is summarized along with types of responses that can be observed in such hybrid systems. This work identifies promising inorganic material types along with target microorganisms that will be critical for future research on programmable biointerfacial structures.

Critical discovery and synthesis of novel antibacterial and resistance-modifying agents inspired by plant phytochemical defense mechanisms.

Antimicrobial resistance is at increasing risk worldwide since it is threatening the ability to control common infectious diseases, resulting in prolonged illness, disability, and death. Herein, we inspired by the effective plant phytochemical mechanisms evolved to overcome microbial pathogenesis and evolved resistance. Cuminaldehyde is previously reported as the main antibacterial component in Calligonum comosum essential oil. The toxicity of cuminaldehyde limits its medical application for human use. On the other hand, compared to cuminaldehyde, the plant total extract showed similar antibacterial activities, while maintained lower toxicity, although it contains 22 times less cuminaldehyde. Thus, we assumed that other components in the plant extracts specifically affect bacteria but not mammalian cells. Bioassay-guided fractionations combined with comparative metabolomics analysis of different plant extracts were employed. The results revealed the presence of bacterial species-specific phytochemicals. Cinnamyl linoleate and linoleic acid enhanced the antibacterial activities of cuminaldehyde and ampicillin against S. aureus including MRSA, while decanal and cinnamyl linoleate enhanced the activities against E. coli. Computational modeling and enzyme inhibition assays indicated that cinnamyl linoleate selectively bind to bacterial ribosomal RNA methyltransferase, an important enzyme involved in the virulence and resistance of multidrug resistant bacteria. The results obtained can be employed for the future preparation of pharmaceutical formula containing cinnamyl linoleate in order to overcome evolved multidrug resistance behaviors by microbes.

Cell-based 3D bionic screening by mimicking the drug-receptor interaction environment in vivo.

Most small-molecule drugs influence cell behavior through their interaction with one or more cellular proteins. The efficacy is unanticipated in the later stages of drug development if small-molecule drugs are discovered in the absence of a biological context. Bionic screening is an in vivo drug-receptor interaction platform that can identify small molecules with recognized activity, improving the likelihood of drug efficacy in the clinic. Here, we report the design of an innovative cell-based bionic screening system using 3D microcarrier cultures to simulate in vivo conditions and facilitate small-molecule drug discovery. Through its combination with HPLC/MS, the method can comprehensively identify small-molecule lead compounds in arbitrarily complex systems in an unbiased manner. In particular, cell-covered microcarriers provide a high-density of cells for affinity performance assessments in the absence of appreciable cell damage and maintain immunogenicity, the 3D structure of which is similar to tissue morphology in vivo, thereby mimicking in vivo drug-receptor interactions. The method is scalable, easy to handle, and requires minimal optimization across a range of different cell lines to realize high-throughput drug screening for the corresponding diseases. This provides a valuable tool for lead compound discovery in more physiologically relevant systems and may address the lack of clinically available drugs.

GSH-Depleted Nanozymes with Hyperthermia-Enhanced Dual Enzyme-Mimic Activities for Tumor Nanocatalytic Therapy.

Nanocatalytic therapy, using artificial nanoscale enzyme mimics (nanozymes), is an emerging technology for therapeutic treatment of various malignant tumors. However, the relatively deficient catalytic activity of nanozymes in the tumor microenvironment (TME) restrains their biomedical applications. Here, a versatile and bacteria-like PEG/Ce-Bi@DMSN nanozyme is developed by coating uniform Bi2 S3 nanorods (NRs) with dendritic mesoporous silica (Bi2 S3 @DMSN) and then decorating ultrasmall ceria nanozymes into the large mesopores of Bi2 S3 @DMSN. The nanozymes exhibit dual enzyme-mimic catalytic activities (peroxidase-mimic and catalase-mimic) under acidic conditions that can regulate the TME, that is, simultaneously elevate oxidative stress and relieve hypoxia. In addition, the nanozymes can effectively consume the overexpressed glutathione (GSH) through redox reaction. Photothermal therapy (PTT) is introduced to synergistically improve the dual enzyme-mimicking catalytic activities and depletion of the overexpressed GSH in the tumors by photonic hyperthermia. This is achieved by taking advantage of the desirable light absorbance in the second near-infrared (NIR-II) window of the PEG/Ce-Bi@DMSN nanozymes. Subsequently the reactive oxygen species (ROS)-mediated therapeutic efficiency is significantly improved. Therefore, this study provides a proof of concept of hyperthermia-augmented multi-enzymatic activities of nanozymes for tumor ablation.

Bioinspired red blood cell membrane-encapsulated biomimetic nanoconstructs for synergistic and efficacious chemo-photothermal therapy.

Recently, the fabrication of nanotechnology-based co-delivery systems has garnered enormous interest for efficacious cancer therapy. However, these systems still face certain challenges such as codelivery of drugs with different chemistries, inadequate loading efficiency, immune rejection resulting in rapid clearance and substantially poor bioavailability in vivo. To address the challenges, we have developed a biomimetic and stable design based on bovine serum albumin (BSA) nanoparticles that are encapsulated with a hydrophilic photothermal agent, indocyanine green (ICG), as well as a hydrophobic agent, gambogic acid (GA), via the desolvation method. Furthermore, these nanoconstructs have been coated with the red blood cell membranes (RBCm), which exhibit pronounced long-term circulation in addition to avoiding premature leakage of drugs. RBCm-coated BSA nanoparticles show a higher affinity towards both GA and ICG (RmGIB NPs), resulting in high loading efficiencies of 24.3 ±â€¯1.2 % and 25.0 ±â€¯1.2 %, respectively. Moreover, the bio-efficacy investigations of these biomimetic constructs (RmGIB NPs) in cells in vitro as well as in tumor-bearing mice in vivo confirm augmented inhibition, demonstrating potential synergistic chemo-photothermal therapeutic efficacy. Altogether, we provide an efficient delivery platform for designing and constructing BSA nanovehicles toward synergistic and effective co-delivery of therapeutics.

A biomimetic MOF nanoreactor enables synergistic suppression of intracellular defense systems for augmented tumor ablation.

A homotypic cancer cell membrane camouflaged MOF-based nanoreactor with the photothermal-starvation effect has been developed for synergistic suppression of intracellular defensive systems for enhanced cancer treatment.

Task-Specific Design of Immune-Augmented Nanoplatform to Enable High-Efficiency Tumor Immunotherapy.

Potentiating systemic immunity against breast cancer is in the most urgent demand as breast cancer is less sensitive to immune checkpoint blockade. Although phototherapy and some chemotherapy can trigger immunogenic cell death (ICD) for T cell-mediated antitumor immune response, their immunotherapy efficacy is severely restricted by insufficient phototherapeutic capability and severe multidrug resistance (MDR). Inspired by both the hypersensitivity to phototherapy and the key role of MDR for mitochondria, a rationally engineered immunity amplifier via mitochondria-targeted photochemotherapeutic nanoparticles was, for the first time, achieved to fight against low-immunogenic breast cancer without additional immune agents. The newly synthesized task-specific mitochondria-targeted IR780 derivative (T780) was integrated with chemotherapeutic doxorubicin (DOX) to form multifunctional nanoparticles via an assembling strategy along with bovine serum albumin (BSA) as a biomimetic corona (BSA@T780/DOX NPs). The in situ enhancement in both phototherapy and MDR reversal by targeting mitochondria with BSA@T780/DOX NPs boosted highly efficient ICD toward excellent antitumor immune response. The newly developed strategy not only eradicated the primary tumor but also eliminated the bilateral tumors efficiently, as well as preventing metastasis and postsurgical recurrence, demonstrating great interest for fighting against low-immunogenic breast cancer.

A Textile Platform Using Continuous Aligned and Textured Composite Microfibers to Engineer Tendon-to-Bone Interface Gradient Scaffolds.

Tendon-to-bone interfaces exhibit a hierarchical multitissue transition. To replicate the progression from mineralized to nonmineralized tissue, a novel 3D fibrous scaffold is fabricated with spatial control over mineral distribution and cellular alignment. For this purpose, wet-spun continuous microfibers are produced using polycaprolactone (PCL)/ gelatin and PCL/gelatin/hydroxyapatite nano-to-microparticles (HAp). Higher extrusion rates result in aligned PCL/gelatin microfibers while, in the case of PCL/gelatin/HAp, the presence of minerals leads to a less organized structure. Biological performance using human adipose-derived stem cells (hASCs) demonstrates that topography of PCL/gelatin microfibers can induce cytoskeleton elongation, resembling native tenogenic organization. Matrix mineralization on PCL/gelatin/HAp wet-spun composite microfibers suggest the production of an osteogenic-like matrix, without external addition of osteogenic medium supplementation. As proof of concept, a 3D gradient structure is produced by assembling PCL/gelatin and PCL/gelatin/HAp microfibers, resulting in a fibrous scaffold with a continuous topographical and compositional gradient. Overall, the feasibility of wet-spinning for the generation of continuously aligned and textured microfibers is demonsrated, which can be further assembled into more complex 3D gradient structures to mimic characteristic features of tendon-to-bone interfaces.

Biomimetic Synthesis of Ag2 Se Quantum Dots with Enhanced Photothermal Properties and as "Gatekeepers" to Cap Mesoporous Silica Nanoparticles for Chemo-Photothermal Therapy.

Ag2 Se quantum dots (QDs) with near-infrared (NIR) fluorescence have been widely utilized in NIR fluorescence imaging in vivo because of their narrow bulk band gap and excellent biocompatibility. However, most of synthesis methods for Ag2 Se QDs are expensive and the reactants are toxic. Herein, a new protein-templated biomimetic synthesis approach is proposed for the preparation of Ag2 Se QDs by employing bovine serum albumin (BSA) as a template and dispersant. The BSA-templated Ag2 Se QDs (Ag2 Se@BSA QDs) showed NIR fluorescence with high fluorescence quantum yield (≈21.2 %), excellent biocompatibility and good dispersibility in different media. Moreover, the obtained Ag2 Se@BSA QDs exhibited remarkable photothermal conversion (≈27.8 %), which could be used in photothermal therapy. As a model application in biomedicine, the Ag2 Se@BSA QDs were used as "gatekeepers" to cap mesoporous silica nanoparticles (MSNs) by means of electrostatic interaction. By taking the advantages of NIR fluorescence and photothermal property of Ag2 Se@BSA QDs, the obtained MSN-DOX-Ag2 Se nanoparticles (MDA NPs) were employed as a nanoplatform for combined chemo-photothermal therapy. Compared with free DOX and MDA NPs without NIR laser, the laser-treated MDA NPs exhibited lower cell viability in vitro, implying that Ag2 Se@BSA QDs are highly promising photothermal agents and the MDA NPs are potential carriers for chemo-photothermal therapy.

Beyond the Roles in Biomimetic Chemistry: An Insight into the Intrinsic Catalytic Activity of an Enzyme for Tumor-Selective Phototheranostics.

Protein-assisted biomimetic synthesis has been an emerging offshoot of nanofabrication in recent years owing to its features of green chemistry, facile process, and ease of multi-integration. As a result, many proteins have been used for biomimetic synthesis of varying kinds of nanostructures. Although the efforts on exploring new proteins and investigating their roles in biomimetic chemistry are increasing, the most essential intrinsic properties of proteins are largely neglected. Herein we report a frequently used enzyme (horseradish peroxidase, HRP) to demonstrate the possibility of enzymatic activity retaining after accomplishing the roles in biomimetic synthesis of ultrasmall gadolinium (Gd) nanodots and stowing its substrate 2,2'-Azinobis (3-ethylbenzothiazoline-6-sulfonic acid ammonium salt) (ABTS), denoted as Gd@HRPABTS. It was found that ca. 70% of the enzymatic activity of HRP was preserved. The associated changes of protein structure with chemical treatments were studied by spectroscopic analysis. Leveraging on the highly retained catalytic activity, Gd@HRPABTS exerts strong catalytic oxidation of peroxidase substrate ABTS into photoactive counterparts in the presence of intrinsic H2O2 inside the tumor, therefore enabling tumor-selective catalytic photoacoustic (PA) imaging and photothermal therapy (PTT). In addition, the MR moiety of Gd@HRPABTS provides guidance for PTT and further diagrams that Gd@HRPABTS is clearable from the body via kidneys. Preliminary toxicity studies show no observed adverse effects by administration of them. This study demonstrates beyond the well-known roles in biomimetic chemistry that HRP can also preserve its enzymatic activity for tumor catalytic theranostics.

Preparation and Characterization of Resveratrol Loaded Pectin/Alginate Blend Gastro-Resistant Microparticles.

BACKGROUND: The use of resveratrol as a dietary supplement is limited because it is easily oxidized and, after oral ingestion, it is metabolized into enterocytes and hepatocytes. Thus, new formulations are needed in order to improve its oral bioavailability. OBJECTIVE: The objective of this study was to develop and characterize a gastro-resistant formulation of resveratrol for oral administration as a dietary supplement. METHOD: Resveratrol was encapsulated in Eudragit-coated pectin-alginate microparticles. RESULTS: The microparticle size was about 1450 µm, with an encapsulation efficiency of 41.72% ± 1.92%. The dissolution assay conducted, as specified in the European Pharmacopoeia for delayed-release dosage forms, revealed that our microparticles were gastro-resistant, because the resveratrol percentage released from microparticles in acid medium was less than 10%. In addition, the high-performance liquid chromatographic (HPLC) method developed for resveratrol content quantification in the microparticles was validated according to International Council for Harmonisation (ICH) Q2 (R1) guidelines. Finally, the biological activity of resveratrol was investigated in 3T3-L1 mature adipocytes, concluding that the encapsulation process does not affect the activity of resveratrol. CONCLUSION: In summary, the gastro-resistant microparticles developed could represent a suitable method of including resveratrol in dietary supplements and in functional foods used in obesity therapy.

Natural Product-Based Pesticide Discovery: Design, Synthesis and Bioactivity Studies of N-Amino-Maleimide Derivatives.

Natural products are an important source of pesticide discovery. A series of N-amino-maleimide derivatives containing hydrazone group were designed and synthesized based on the structure of linderone and methyllinderone which were isolated from Lindera erythrocarpa Makino. According to the bioassay results, compounds 2 and 3 showed 60% inhibition against mosquito (Culex pipiens pallens) at 0.25 µg·mL−1. Furthermore, the results of antifungal tests indicated that most compounds exhibited much better antifungal activities against fourteen phytopathogenic fungi than linderone and methyllinderone and some compounds exhibited better antifungal activities than commercial fungicides (carbendazim and chlorothalonil) at 50 µg·mL−1. In particular, compound 12 exhibited broad-spectrum fungicidal activity (>50% inhibitory activities against 11 phytopathogenic fungi) and compounds 12 and 14 displayed 60.6% and 47.9% inhibitory activity against Rhizoctonia cerealis at 12.5 µg·mL−1 respectively. Furthermore, compound 17 was synthesized, which lacks N-substituent at maleimide and its poor antifungal activity against Sclerotinia sclerotiorum and Rhizoctonia cerealis at 50 µg·mL−1 showed that the backbone structure of N-amino-maleimide derivatives containing hydrazone group was important to the antifungal activity.

Cyclic uniaxial compression of human stem cells seeded on a bone biomimetic nanocomposite decreases anti-osteogenic commitment evoked by shear stress.

OBJECTIVE: Chemical supplementation of culture media to induce differentiation of adult stem cells seeded on a scaffold may mask other differentiation triggers such as scaffold stiffness, chemical composition or mechanical stimulation. However, stem cells can be differentiated towards osteoblasts without any supplementation given an appropriate osteogenic scaffold and an adequate mechanical stimulation. MATERIALS AND METHODS: Electrospun meshes of poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles (PLGA/aCaP) in a weight ratio of 60:40 were seeded with human adipose-derived stem cells (ASCs) and cultured in DMEM. After two weeks of static cultivation, they were either further cultivated statically for another two weeks (group 1), or placed in a Bose® bioreactor with a flow rate per area of 0.16 mL cm-2 min1 (group 2). Furthermore, group 3 was also cultivated under perfusion, however, with an additional uniaxial cyclic compression. Stiffness of the scaffolds was assessed as a function of time. After a total of four weeks, minimum stem cell criteria markers as well as typical markers for osteogenesis, endothelial cell differentiation, adipogenesis and chondrogenesis were analyzed by quantitative real-time PCR, cell distribution within the scaffolds by histology and protein expression by immunohistochemistry. RESULTS: Dynamic conditions (perfusion ±â€¯uniaxial cyclic compression) significantly upregulated gene and protein expression of PPAR-γ-2 compared to static cultivation, while osteogenic markers were slightly downregulated. However, the compression in the perfusion bioreactor favored osteogenesis compared to mere perfusion as indicated by upregulation of ALP, Runx2 and collagen I. This behavior was not only attributed to the compressive load, but also to the significant increase in stiffness of the scaffold. Furthermore, CD105 was significantly upregulated under compression. CONCLUSIONS: Although an osteogenic electrospun composite material with an organic (PLGA) and an inorganic phase (aCaP nanoparticles) was used as scaffold, the dynamic cultivation as realized by either perfusion alone or an additional compression did not upregulate typical osteogenic genes when compared to static cultivation. In contrast, there was a significant upregulation of the adipogenic gene PPAR-γ-2. However, this anti-osteogenic starting point evoked by mere perfusion was partially reversed by an additional compression. Our findings exemplify that bone tissue engineering using adult stem cells should consider any other differentiations that may be triggered and overwhelm the desired differentiation, although experimental conditions theoretically provide cues to achieve it - like an osteogenic scaffold and mechanical stimulation.

BMX-001, a novel redox-active metalloporphyrin, improves islet function and engraftment in a murine transplant model.

Islet transplantation has become a well-established therapy for select patients with type 1 diabetes. Viability and engraftment can be compromised by the generation of oxidative stress encountered during isolation and culture. We evaluated whether the administration of BMX-001 (MnTnBuOE-2-PyP5+ [Mn(III) meso-tetrakis-(N-b-butoxyethylpyridinium-2-yl)porphyrin]) and its earlier derivative, BMX-010 (MnTE-2-PyP [Mn(III) meso-tetrakis-(N-methylpyridinium-2-yl)porphyrin]) could improve islet function and engraftment outcomes. Long-term culture of human islets with BMX-001, but not BMX-010, exhibited preserved in vitro viability. Murine islets isolated and cultured for 24 hours with 34 µmol/L BMX-001 exhibited improved insulin secretion (n = 3 isolations, P < .05) in response to glucose relative to control islets. In addition, 34 µmol/L BMX-001-supplemented murine islets exhibited significantly reduced apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling, compared with nontreated control islets (P < .05). Murine syngeneic islets transplanted under the kidney capsule at a marginal dose of 150 islets revealed 58% of 34 µmol/L BMX-001-treated islet recipients became euglycemic (n = 11 of 19) compared with 19% of nontreated control islet recipients (n = 3 of 19, P < .05). Of murine recipients receiving a marginal dose of human islets cultured with 34 µmol/L BMX-001, 92% (n = 12 of 13) achieved euglycemia compared with 57% of control recipients (n = 8 of 14, P = .11). These results demonstrate that the administration of BMX-001 enhances in vitro viability and augments murine marginal islet mass engraftment.

Design of Carrageenan-Based Heparin-Mimetic Gel Beads as Self-Anticoagulant Hemoperfusion Adsorbents.

The currently used hemoperfusion adsorbents such as activated carbon and ion-exchange resin show dissatisfactory hemocompatibility, and a large dose of injected heparin leads to the increasing cost and the risk of systematic bleeding. Natural polysaccharide adsorbents commonly have good biocompatibility, but their application is restricted by the poor mechanical strength and low content of functional groups. Herein, we developed an efficient, self-anticoagulant and blood compatible hemoperfusion adsorbent by imitating the structure and functional groups of heparin. Carrageenan and poly(acrylic acid) (PAA) cross-linked networks were built up by the combination of phase inversion of carrageenan and post-cross-linking of AA, and the formed dual-network structure endowed the beads with improved mechanical properties and controlled swelling ratios. The beads exhibited low protein adsorption amounts, low hemolysis ratios, low cytotoxicity, and suppressed complement activation and contact activation levels. Especially, the activated partial thromboplastin time, prothrombin time, and thrombin time of the gel beads were prolonged over 13, 18, and 4 times than those of the control. The self-anticoagulant and biocompatible beads showed good adsorption capacities toward exogenous toxins (560.34 mg/g for heavy metal ions) and endogenous toxins (14.83 mg/g for creatinine, 228.16 mg/g for bilirubin, and 18.15 mg/g for low density lipoprotein (LDL)), thus, highlighting their potential usage for safe and efficient blood purification.