Mussel shell-derived pro-regenerative scaffold with conductive porous multi-scale-patterned microenvironment for spinal cord injury repair.

It is well-established that multi-scale porous scaffolds can guide axonal growth and facilitate functional restoration after spinal cord injury (SCI). In this study, we developed a novel mussel shell-inspired conductive scaffold for SCI repair with ease of production, multi-scale porous structure, high flexibility, and excellent biocompatibility. By utilizing the reducing properties of polydopamine, non-conductive graphene oxide (GO) was converted into conductive reduced graphene oxide (rGO) and crosslinkedin situwithin the mussel shells.In vitroexperiments confirmed that this multi-scale porous Shell@PDA-GO could serve as structural cues for enhancing cell adhesion, differentiation, and maturation, as well as promoting the electrophysiological development of hippocampal neurons. After transplantation at the injury sites, the Shell@PDA-GO provided a pro-regenerative microenvironment, promoting endogenous neurogenesis, triggering neovascularization, and relieving glial fibrosis formation. Interestingly, the Shell@PDA-GO could induce the release of endogenous growth factors (NGF and NT-3), resulting in the complete regeneration of nerve fibers at 12 weeks. This work provides a feasible strategy for the exploration of conductive multi-scale patterned scaffold to repair SCI.

3D sponge loaded with cisplatin-CS-calcium alginate MPs utilized as a void-filling prosthesis for the efficient postoperative prevention of tumor recurrence and metastasis.

Intraoperative bleeding is a pivotal factor in the initiation of early recurrence and tumor metastasis following breast cancer excision. Distinct advantages are conferred upon postoperative breast cancer treatment through the utilization of locally administered implant therapies. This study devised a novel 3D sponge implant containing cisplatin-loaded chitosan-calcium alginate MPs capable of exerting combined chemotherapy and hemostasis effects. This innovative local drug-delivery implant absorbed blood and residual tumor cells post-tumor resection. Furthermore, the cisplatin-loaded chitosan-calcium alginate MPs sustainably targeted and eliminated cancer cells, thereby diminishing the risk of local recurrence and distant metastasis. This hydrogel material can also contribute to breast reconstruction, indicating the potential application of the 3D sponge in drug delivery for breast cancer treatment.

Cardiac-Adaptive Conductive Hydrogel Patch Enabling Construction of Mechanical-Electrical Anisotropic Microenvironment for Heart Repair.

The biomimetic construction of a microstructural-mechanical-electrical anisotropic microenvironment adaptive to the native cardiac tissue is essential to repair myocardial infarction (MI). Inspired by the 3D anisotropic characteristic of the natural fish swim bladder (FSB), a novel flexible, anisotropic, and conductive hydrogel was developed for tissue-specific adaptation to the anisotropic structural, conductive, and mechanical features of the native cardiac extracellular matrix. The results revealed that the originally stiff, homogeneous FSB film was tailored to a highly flexible anisotropic hydrogel, enabling its potential as a functional engineered cardiac patch (ECP). In vitro and in vivo experiments demonstrated the enhanced electrophysiological activity, maturation, elongation, and orientation of cardiomyocytes (CMs), and marked MI repair performance with reduced CM apoptosis and myocardial fibrosis, thereby promoting cell retention, myogenesis, and vascularization, as well as improving electrical integration. Our findings offer a potential strategy for functional ECP and provides a novel strategy to bionically simulate the complex cardiac repair environment.

3D hypoxia-mimicking and anti-synechia hydrogel enabling promoted neovascularization for renal injury repair and regeneration.

In-situ renal tissue engineering is promising yet challenging for renal injury repair and regeneration due to the highly vascularized structure of renal tissue and complex high-oxidative stress and ischemic microenvironment. Herein, a novel biocompatible 3D porous hydrogel (DFO-gel) with sustained release capacity of hypoxia mimicking micromolecule drug deferoxamine (DFO) was developed for in-situ renal injury repair. In vitro and in vivo experimental results demonstrated that the developed DFO-gels can exert the synchronous benefit of scavenging excess reactive oxygen species (ROS) regulating inflammatory microenvironment and promoting angiogenesis for effective renal injury repair by up-regulating hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF). The in-situ neogenesis of neonatal glomerular- and tubular-like structures in the implanted areas in the partially nephrectomized rats also suggested the potential for promoting renal injury repair and regeneration. This multifunctional hydrogel can not only exhibit the sustained release and promoted bio-uptake capacity for DFO, but also improve the renal injured microenvironment by alleviating oxidative and inflammatory stress, accelerating neovascularization, and promoting efficient anti-synechia. We believe this work offers a promising strategy for renal injury repair and regeneration.

A 3D-printed bioactive polycaprolactone scaffold assembled with core/shell microspheres as a sustained BMP2-releasing system for bone repair.

Integration of biological factors and hierarchical rigid scaffolds is of great interest in bone tissue engineering for fabrication of biomimetic constructs with high physical and biological performance for enhanced bone repair. Core/shell microspheres (CSMs) delivering bone morphogenetic protein-2 (BMP-2) and a strategy to integrate CSMs with 3D-printed scaffolds were developed herein to form a hybrid 3D system for bone repair. The scaffold was printed with polycaprolactone (PCL) and then coated with polydopamine. Shells of CSMs were electrosprayed with alginate. Cores were heparin-coated polylactic acid (PLA) microparticles fabricated via simple emulsion and heparin coating strategy. Assembly of microspheres and scaffolds was realized via a self-locking method with the assistance of controlled expansion of CSMs. The hybrid system was evaluated in the rat critical-sized bone defect model. CSMs released BMP-2 in a tunable manner and boosted osteogenic performance in vitro. CSMs were then successfully integrated inside the scaffolds. The assembled system effectively promoted osteogenesis in vitro and in vivo. These observations show the importance of how BMP-2 is delivered, and the core/shell microspheres represent effective BMP-2 carriers that could be integrated into scaffolds, together forming a hybrid system as a promising candidate for enhanced bone regeneration.

Injectable and conductive cardiac patches repair infarcted myocardium in rats and minipigs.

Cardiac patches can help to restore the electrophysiological properties of the heart after myocardial infarction. However, scaffolds for the repair of heart muscle typically require surgical implantation or, if they are injectable, they are not electrically conductive or do not maintain their shape or function. Here, we report the performance, as demonstrated for the repair of infarcted heart muscle in rats and minipigs, of injectable and conductive scaffolds consisting of methacrylated elastin and gelatin, and carbon nanotubes that display shape-memory behaviour, a hierarchical porous structure and a negligible Poisson's ratio. In rats, the implantation of cell-free patches or patches seeded with rat cardiomyocytes onto the myocardium after ligation of the left anterior descending coronary artery led to functional repair after 4 weeks, as indicated by increases in fractional shortening and the ejection fraction, and by a decrease in the infarcted area. We also observed measures of functional recovery in minipigs with infarcted hearts after the delivery of cell-free patches or patches incorporating cardiomyocytes differentiated from human pluripotent stem cells.

A tunable self-healing ionic hydrogel with microscopic homogeneous conductivity as a cardiac patch for myocardial infarction repair.

Conductive hydrogel is a potential therapeutic tool to treat damaged heart muscles in myocardial infarction (MI). However, it is still a quite challenge to optimize the fabrication of a therapeutic hydrogel patch that sustains favorable biocompatibility, electronic and mechanical stability under a complicated MI microenvironment. Herein, a tunable self-healing ionic hydrogel (POG1) was developed through the introduction of a biocompatible polyacrylic acid (PAA, FDA-approved) into the hydrogel matrix. The fabricated POG1 hydrogel possessed suitable stretchable (>500% strain) and compressive (>85% strain) properties, comparable modulus with mammalian heart (30-500 kPa, Young's modulus), self-healable, and highly stable conductivity during large deformations (~50% compress strain, ~150% tensile strain). Specifically, the established PAA nano-channels inside of POG1 endowed the hydrogel with microscopic ultra-homogeneous conductivity. Compared to those seeded in the electronic conductors-embedded (PPy, CNT, rGO) hydrogels, the cardiomyocytes (CMs) seeded in the POG1 hydrogel exhibited more significantly oriented sarcomeres. This POG1 engineered cardiac patch (ECP) also exerted robust benefits in attenuating left ventricular remodeling and restoring heart function after implantation in vivo. This paper highlighted a previously unexplored strategy for a biocompatible ionic conductive hydrogel ECP with an excellent MI repair function.

Mussel-inspired conductive Ti2C-cryogel promotes functional maturation of cardiomyocytes and enhances repair of myocardial infarction.

Rationale: Researches on conductive engineering cardiac patch (ECP) for myocardial infarction (MI) treatment have achieved some progress in the animal while the availability of traditional conductive materials in ECP is still limited because of their controversial cytotoxicity. Here we aim to introduce a novel hydrophilic biocompatible conductive material: MXene Ti2C and mussel-inspired dopamine into PEGDA-GelMA cryogel to construct a bio-functional ECP of which the property closes to natural heart for the repair of MI. Method: MXene Ti2C was etched from MAX Ti2AlC, then uniformly dispersed into the prepolymer composed with dopamine-N', N'-methylene-bisacrylamide, methacrylate-gelatin, and poly (ethylene glycol) diacrylate by simple water bath sonication. The resilient conductive Ti2C-cryogel was fabricated by chemical cryogelation. The conductive ECP was evaluated in vitro and transplanted to the MI rat model for MI treatment. Results: In vitro, the 3D vessels-shape framework was observed in Ti2C-8-cryogel which was seeded with rats aortic endothelial cells. When the Ti2C-cryogels were cocultured with CMs, remarkably aligned sarcomere and the primitive intercalated disc between the mature CMs were formed on day 7. The as-prepared Ti2C-8-cryogel ECP also demonstrated rapid calcium transients and synchronous tissue-like beating. When transplanted into the infarcted heart of the MI rat model, the Ti2C-8-cryogel ECP could improve the cardiac function, reduce the infarct size, and inhibit the inflammatory response. Obvious vasculation especially newly formed arteriole was also found. Conclusion: A novel conductive Ti2C-embedded cardiac patch with suitable conductivity and the mechanical property was developed and could be served as an ideal candidate for MI repair.

A Humanized Cancer-Bone Metastasis Mouse Model Based on Silica Nanoparticles-Incorporated Human Demineralized Bone Matrix.

Breast cancer tends to spread to other organs and bone metastasis has the highest frequency in breast cancer metastasis, while its mechanisms are not clear and the current treatments are not very effective. To better study the mechanisms and facilitate drug screening for breast cancer bone metastasis, an in vivo mouse model needs to be constructed. However, the construction of the humanized mouse model for cancer bone metastasis which will mimick real interactions between cancer tissue and bone tissue in the human microenvironment remains a challenge. In this study, we constructed a human engineering bone tissue composed with the human osteoblast-like cells (SaOS-2 cells) and the silica nanoparticlesincorporated human demineralized bone matrix (Si/DBM). The engineered bone was then transplanted into a nude mouse to build a humanized bone microenvironment. The human breast cancer cells were then injected into the fat pads of the nude mouse to form an orthotopic tumor. The results showed that the engineered bone tissue-constructed humanized bone microenvironment had significant advantages when inducing human cancer cells to metastasize into the engineered bone tissue. Further, the SaOS-2/Si/DBM had a stronger ability to entice cancer-bone metastasis through promoting osteogenesis compared to the SaOS-2/DBM. Accordingly, this study highlights a novel, facile and effective mouse model for human cancer-bone metastasis, which will provide a platform to explore the mechanisms and anti-tumor drug screening for cancer-bone metastasis.

Mussel-inspired conductive nanofibrous membranes repair myocardial infarction by enhancing cardiac function and revascularization.

The controversy between polypyrrole's (Ppy) biocompatibility and its aggregation on nanofibers impedes application of conductive Ppy-incorporated nanofibers to create engineered cardiac microenvironments. The purpose of this study was to fabricate a functional scaffold for engineering cardiac patches (ECP) using a high concentration of methyl acrylic anhydride-gelatin (GelMA)-Ppy nanoparticles, mussel-inspired crosslinker, and electrospun (ES)-GelMA/polycaprolactone (PCL) nanofibrous membrane. Methods: First, spherical GelMA-Ppy nanoparticles were obtained when the methacrylate groups of GelMA formed a self-crosslinked network through oxidative polymerization of Ppy. Second, GelMA-Ppy nanoparticles were uniformly crosslinked on the ES-GelMA/PCL membrane through mussel-inspired dopamine-N'N'-methylene-bis-acrylamide (dopamine-MBA) crosslinker. Finally, the feasibility of the dopa-based conductive functional ECP scaffold was investigated in vitro and in vivo. Results: The GelMA-Ppy nanoparticles displayed excellent biocompatibility at a high concentration of 50 mg/mL. The massive GelMA-Ppy nanoparticles could be uniformly distributed on the ES nanofibers through dopamine-MBA crosslinker without obvious aggregation. The high concentration of GelMA-Ppy nanoparticles produced high conductivity of the dopamine-based (dopa-based) conductive membrane, which enhanced the function of cardiomyocytes (CMs) and yielded their synchronous contraction. GelMA-Ppy nanoparticles could also modify the topography of the pristine ES-GelMA/PCL membrane to promote vascularization in vitro. Following transplantation of the conductive membrane-derived ECP on the infarcted heart for 4 weeks, the infarct area was decreased by about 50%, the left ventricular shortening fraction percent (LVFS%) was increased by about 20%, and the neovascular density in the infarct area was significantly increased by about 9 times compared with that in the MI group. Conclusion: Our study reported a facile and effective approach to developing a functional ECP that was based on a mussel-inspired conductive nanofibrous membrane. This functional ECP could repair infarct myocardium through enhancing cardiac function and revascularization.

Residual Ammonium Persulfate in Nanoparticles Has Cytotoxic Effects on Cells through Epithelial-Mesenchymal Transition.

Ammonium persulfate (APS), a low molecular weight chemical compound with strong oxidizing properties, should to be totally removed during preparation of nanomaterials due to its cytotoxicity. APS exerts its oxidative stress effects mainly on cell membrane, but its intracellular influence remains unclear. Here, we designed a facile negatively-charged carboxylic gelatin-methyacrylate (carbox-GelMA) nanoparticle (NP) as a cargo-carrier through the catalytic and oxidizing action of APS in W/O system. The formed APS-loaded carbox-GelMA NPs (APS/NPs) were transported into the lysosome in MCF-7 breast cancer cells. The intracellular APS/NPs produced a high level of oxidative stress in lysosome and induced epithelial-mesenchymal transition (EMT). Consequently, the MCF-7 cells challenged with APS/NPs had a strong metastatic and invasive capability in vitro and in vivo. This study highlights that a facile APS-loaded nanocarrier has cyctotoxicity on cells through EMT. Unexpectedly, we found a novel pathway inducing EMT via lysosomal oxidative stress.