Focused ultrasound-mediated cerium-based nanoreactor against Parkinson's disease via ROS regulation and microglia polarization.

Neuronal damage caused by oxidative stress and inflammatory microenvironment dominated by microglia are the main obstacles in the treatment of Parkinson's disease (PD). In this study, we developed an integrated nanoreactor Q@CeBG by encapsulating CeO2 nanozyme and quercetin (Que) into glutathione-modified bovine serum albumin, and then selected focused ultrasound (FUS) to temporarily open the blood-brain barrier (BBB) to enhance the accumulation level of Q@CeBG in the brain. Q@CeBG exhibited superior multi-ROS scavenging activity. Under the assistance of FUS, Q@CeBG nanoreactor can penetrate the BBB and act on neurons as well as microglia, reducing the neuron's oxidative stress level and polarizing microglia's phenotype from proinflammatory M1 to anti-inflammatory M2. In vitro and In vivo experiments demonstrated that Q@CeBG nanoreactor with good biocompatibility exhibit outstanding neuroprotection and immunomodulatory effects. In short, this dual synergetic nanoreactor will become a reliable platform against PD.

Mitomycin C-loaded PTMC15-F127-PTMC15 hydrogel maintained better bleb function after filtering glaucoma surgery in monkeys with intraocular hypertension.

There is an unmet need for a safer and more effective approach for antimetabolite application to prevent bleb fibrosis after glaucoma filtering surgery. Here, we utilized our previously developed thermosensitive sustained-release agent, mitomycin C-loaded poly(trimethylene carbonate)15-F127-poly(trimethylene carbonate)15 (MMC-hydrogel), aiming to further evaluate the efficacy and safety of MMC-hydrogel in high intraocular pressure (IOP) primate eyes. Twelve primate eyes after high IOP induction were randomly divided into three groups, which respectively received phosphate-buffered saline (PBS)-hydrogel, MMC-hydrogel, and MMC treatment during trabeculectomy. IOP and bleb volume were measured using a Tonopen and anterior segment optical coherence tomography over 28 days. At the end of the experiment, all experimental primate eyes were enucleated. Histopathology and immunohistochemistry were performed to reveal myofibroblast cells and collagen deposition of filtering blebs. The MMC-hydrogel group had satisfactory IOP control (9.25 ± 4.80 mmHg) and maintained well-functioning blebs for a longer time. Fibrosis and scarring were significantly alleviated in this MMC-hydrogel group. There was no obvious toxicity to ocular surfaces or intraocular structures. Taken together, these data suggest that PTMC15-F127-PTMC15-loaded MMC-hydrogel plays a role in functional maintenance and scarring inhibition, showing high efficacy in reducing post-filtering surgery bleb fibrosis. This MMC-hydrogel may offer a new solution for filtering bleb management after glaucoma surgery.

NIR-Assisted MgO-Based Polydopamine Nanoparticles for Targeted Treatment of Parkinson's Disease through the Blood-Brain Barrier.

The blood-brain barrier (BBB) is a major limiting factor that prevents the treatment of Parkinson's disease (PD). In the present study, MgOp@PPLP nanoparticles are explored by using MgO nanoparticles as a substrate, polydopamine as a shell, wrapping anti-SNCA plasmid inside, and modifying polyethylene glycol, lactoferrin, and puerarin on the surface to improve the hydrophilicity, brain targeting and antioxidant properties of the particles, respectively. MgOp@PPLP exhibits superior near-infrared radiation (NIR) response. Under the guidance of photothermal effect, these MgOp@PPLP particles are capable of penetrating the BBB and be taken up by neuronal cells to exert gene therapy and antioxidant therapy. In both in vivo and in vitro models of PD, MgOp@PPLP exhibits good neuroprotective effects. Therefore, combined with noninvasive NIR radiation, MgOp@PPLP nanoplatform with good biocompatibility becomes an ideal material to combat neurodegenerative diseases.

Construction of a double-responsive modified guar gum nanoparticles and its application in oral insulin administration.

The use of intelligent insulin delivery systems has become more important for treating diabetes. In this study, a dual-responsive oral insulin delivery nanocarrier that responds to glucose and pH has been developed. First, the oleic acid hydrophobic modified guar gum (GG) was synthesized by the esterification reaction, and the γ-polyglutamic acid (γ-PGA) was coupled with GG by the amidation reaction. The obtained pH-responsive copolymer (γ-PGA-GG) was cross-linked by concanavalin A to obtain pH/glucose dual-responsive nanocarriers, and insulin was effectively loaded into the dual-responsive nanocarriers. The insulin-loaded nanoparticles can achieve effective pH and glucose responses, releasing insulin on demand. In vitro and in vivo studies demonstrated the dual-responsive nanoparticles can protect insulin against the pH changes in the digestive tract and deliver insulin into the body to exert a hypoglycemic effect. Moreover, the dual-responsive nanoparticles have significant potential to be employed for oral insulin delivery.

Fabrication of Resveratrol-Loaded Scaffolds and Their Application for Delaying Cell Senescence In Vitro.

In this research, resveratrol (RSV)-loaded scaffolds have been prepared to control the release of resveratrol and used to delay hepatic stellate cell (HSC) senescence in vitro. The functional carboxyl group-COOH is first introduced to the surface of poly(ε-caprolactone/d,l-lactide) (P(CL-DLLA)) under the coadministration of ultra-violet (UV) treatment and photo initiator and then resveratrol are conjugated onto the surface of the modified scaffolds through esterification. The characterization of the structure of RSV-AA-P(CL-DLLA) shows that resveratrol has been successfully conjugated onto the modified surface. Cell growth exhibits a higher level of cell viability and much more obvious agglomeration on the surface of the synthetic RSV-AA-P(CL-DLLA). Meanwhile the activity of senescence-associated ß-galactosidase (SA-ß-gal) and reactive oxygen species (ROS) is downgulated for cells on RSV-AA-P(CL-DLLA), which suggests that cell senescence is delayed on RSV-AA-P(CL-DLLA). And then it is attested that cells have a lower level of p53 but SIRT1 expression is upregulated on RSV-AA-P(CL-DLLA), which might be related to resveratrol release from RSV-AA-P(CL-DLLA). It also suggested cell senescence on RSV-AA-P(CL-DLLA) has been regulated by p53 and the SIRT1 signaling pathway. In all, the present study shows that RSV-AA-P(CL-DLLA) can be successfully prepared to promote cell growth and delay cell senescence and could be used for cell-based therapy in tissue engineering.

Carbon Nanotube Polymer Scaffolds as a Conductive Alternative for the Construction of Retinal Sheet Tissue.

With the great success of graphene in the biomedical field, carbon nanotubes have attracted increasing attention for different applications in ophthalmology. Here, we report a novel retinal sheet composed of carbon nanotubes (CNTs) and poly(lactic-co-glycolic acid) (PLGA) that can enhance retinal cell therapy. By tuning our CNTs to regulate the mechanical characteristics of retina sheets, we were able to improve the in vitro viability of retinal ganglion cells derived from human-induced pluripotent stem cells incorporated into CNTs. Engrafted retinal ganglion cells displayed signs of regenerating processes along the optic nerve. Compared with PLGA scaffolds, CNT-PLGA retinal sheet tissue has excellent electrical conductivity, biocompatibility, and biodegradation. This new biomaterial offers new insight into retinal injury, repair, and regeneration.

Biodegradable scaffolds facilitate epiretinal transplantation of hiPSC-Derived retinal neurons in nonhuman primates.

Transplantation of stem cell-derived retinal neurons is a promising regenerative therapy for optic neuropathy. However, significant anatomic differences compromise its efficacy in large animal models. The present study describes the procedure and outcomes of human-induced pluripotent stem cell (hiPSC)-derived retinal sheet transplantation in primate models using biodegradable materials. Stem cell-derived retinal organoids were seeded on polylactic-coglycolic acid (PLGA) scaffolds and directed toward a retinal ganglion cell (RGC) fate. The seeded tissues showed active proliferation, typical neuronal morphology, and electrical excitability. The cellular scaffolds were then epiretinally transplanted onto the inner surface of rhesus monkey retinas. With sufficient graft-host contact provided by the scaffold, the transplanted tissues survived for up to 1 year without tumorigenesis. Histological examinations indicated survival, further maturation, and migration. Moreover, green fluorescent protein-labeled axonal projections toward the host optic nerve were observed. Cryopreserved organoids were also able to survive and migrate after transplantation. Our results suggest the potential efficacy of RGC replacement therapy in the repair of optic neuropathy for the restoration of visual function. STATEMENT OF SIGNIFICANCE: In the present study, we generated a human retinal sheet by seeding hiPSC-retinal organoid-derived RGCs on a biodegradable PLGA scaffold. We transplanted this retinal sheet onto the inner surface of the rhesus monkey retina. With scaffold support, donor cells survive, migrate and project their axons into the host optic nerve. Furthermore, an effective cryopreservation strategy for retinal organoids was developed, and the thawed organoids were also observed to survive and show cell migration after transplantation.

Dexamethasone Provides Effective Immunosuppression for Improved Survival of Retinal Organoids after Epiretinal Transplantation.

We investigated the efficacy of the immunosuppressants rapamycin (RAP) and dexamethasone (DEX) in improving the survival of retinal organoids after epiretinal transplantation. We first compared the immunosuppressive abilities of DEX and RAP in activated microglia in an in vitro setting. Following this, we used immunofluorescence, real-time polymerase chain reaction, and flow cytometry to investigate the effects of DEX and RAP on cells in the retinal organoids. Retinal organoids were then seeded onto poly(lactic-co-glycolic) acid (PLGA) scaffolds and implanted into rhesus monkey eyes (including a healthy individual and three monkeys with chronic ocular hypertension (OHT) induction) and subjected to different post-operative immunosuppressant treatments; 8 weeks after the experiment, histological examinations were carried out to assess the success of the different treatments. Our in vitro experiments indicated that both DEX and RAP treatments were equally effective in suppressing microglial activity. Although both immunosuppressants altered the morphologies of cells in the retinal organoids and caused a slight decrease in the differentiation of cells into retinal ganglion cells, the organoid cells retained their capacity to grow and differentiate into retinal tissues. Our in vivo experiments indicate that the retinal organoid can survive and differentiate into retinal tissues in a healthy rhesus monkey eye without immunosuppressive treatment. However, the survival and differentiation of these organoids in OHT eyes was successful only with the DEX treatment. RAP treatment was ineffective in preventing immunological rejection, and the retinal organoid failed to survive until the end of 8 weeks. DEX is likely a promising immunosuppressant to enhance the survival of epiretinal implants.

Effects of Differentiation and Antisenescence from BMSCs to Hepatocy-Like Cells of the PAAm-IGF-1/TNF-α Biomaterial.

Aiming at the cells' differentiation phenomenon and senescence problem in liver tissue engineering, this work is designed to synthesize three different chargeable polymers (polypropylene acid (PAAc), polyethylene glycol (PEG), and polypropylene amine (PAAm)) coimmobilized by the insulin-like growth factor 1 (IGF-1) and tumor necrosis factor-α (TNF-α). We explore the hepatocyte differentiation effect and the antisenecence effect of PSt-PAAm-IGF-1/TNF-α biomaterial which was selected from the three different chargeable polymers in bone marrow mesenchymal stem cells (BMSCs). Our work will establish a model for studying the biochemical molecular regulation mechanism and signal transduction pathway of cell senescence in liver tissue engineering, which provide a molecular basis for developing biomaterials for liver tissue engineering.

Self-Assembled Heterojunction Carbon Nanotubes Synergizing with Photoimmobilized IGF-1 Inhibit Cellular Senescence.

Synthesis of artificial and functional structures for bone tissue engineering has been well recognized but the associated cell senescence issue remains much less concerned so far. In this work, surface-modified polycaprolactone-polylactic acid scaffolds using self-assembled heterojunction carbon nanotubes (sh-CNTs) combined with insulin-like growth factor-1 are synthesized and a series of structural and biological characterizations are carried out, with particular attention to cell senescence mechanism. It is revealed that the modified scaffolds can up-regulate the expressions of alkaline phosphates and bone morphogenetic proteins while down-regulate the expressions of senescence-related proteins in mesenchymal stem cells, demonstrating the highly preferred anti-senescence functionality of the sh-CNTs modified scaffolds in bone tissue engineering. Furthermore, it is also found that with sh-CNTs, scaffolds can accelerate bone healing with extremely low toxicity in vivo.