Advances of nanotechnology for intracerebral hemorrhage therapy.

Intracerebral hemorrhage (ICH), the most devastating subtype of stoke, is of high mortality at 5 years and even those survivors usually would suffer permanent disabilities. Fortunately, various preclinical active drugs have been approached in ICH, meanwhile, the therapeutic effects of these pharmaceutical ingredients could be fully boosted with the assistance of nanotechnology. In this review, besides the pathology of ICH, some ICH therapeutically available active drugs and their employed nanotechnologies, material functions, and therapeutic principles were comprehensively discussed hoping to provide novel and efficient strategies for ICH therapy in the future.

In vivo metabolizable branched poly(ester amide) based on inositol and amino acids as a drug nanocarrier for cancer therapy.

Amino acid-based poly(ester amide) (PEA) has been utilized for various biomedical applications due to its tunable mechanical properties, good biocompatibility, and biodegradability. However, bioactive components have rarely been incorporated into the PEA structure, and there has been no systematic investigation of amino acid-based PEAs with branched structures. Herein, an in vivo metabolizable branched poly(ester amide) (BPEA) was synthesized from inositol (a natural growth factor) and amino acids for drug delivery in cancer therapy. The bioactive components, inositol, arginine, and phenylalanine, could improve the biocompatibility of the BPEA nanocarrier, and convert into other valuable biomolecules (phosphatidylinositol for cell signaling, functional protein, or other amino acids including ornithine, citrulline, and tyrosine) after accomplishing drug delivery and biodegradation. Paclitaxel (PTX) was encapsulated into BPEA nanocarriers to formulate drug-loaded BPEA nanoparticles (BPEA@PTX NPs). In vitro results indicated that BPEA@PTX NPs had a sub 100 nm size and could effectively inhibit the growth and migration of cancer cells. In vivo experiments further demonstrated significant suppression of tumor size compared with that with free PTX. Both in vitro and in vivo results confirmed the superior biosafety of BPEA, indicating that BPEA exhibits excellent biocompatibility and considerable potential as a drug carrier.

Accelerating ESD-induced gastric ulcer healing using a pH-responsive polyurethane/small intestinal submucosa hydrogel delivered by endoscopic catheter.

Endoscopic submucosal dissection (ESD) is the standard treatment for early-stage gastric cancer, but the large post-operative ulcers caused by ESD often lead to serious side effects. Post-ESD mucosal repair materials provide a new option for the treatment of post-ESD ulcers. In this study, we developed a polyurethane/small intestinal submucosa (PU/SIS) hydrogel and investigated its efficacy for accelerating ESD-induced ulcer healing in a canine model. PU/SIS hydrogel possessed great biocompatibility and distinctive pH-sensitive swelling properties and protected GES-1 cells from acid attack through forming a dense film in acidic conditions in vitro. Besides, PU/SIS gels present a strong bio-adhesion to gastric tissues under acidic conditions, thus ensuring the retention time of PU/SIS gels in vivo. In a canine model, PU/SIS hydrogel was easily delivered via endoscopy and adhered to the ulcer sites. PU/SIS hydrogel accelerated gastric ulcer healing at an early stage with more epithelium regeneration and slight inflammation. Our findings reveal PU/SIS hydrogel is a promising and attractive candidate for ESD-induced ulcer repair.

Amino Acid- and Growth Factor-Based Multifunctional Nanocapsules for the Modulation of the Local Microenvironment in Tissue Engineering.

Oxidative damage to cells from metabolites at a wound site is one of the trickiest factors inhibiting tissue regeneration, especially with bulk damage. In addition, an excessive inflammatory reaction by the body at the wound site can make it even worse. How to scavenge the reactive oxygen species (ROS) produced from metabolism and inflammatory reactions has become a critical issue in tissue engineering. Here, we utilize the natural bioactive small molecules l-arginine and l-phenylalanine and the growth factor inositol to synthesize a branched poly(ester amide) (BPEA) to fabricate BPEA nanocapsules for vitamin E delivery at wound sites. BPEA nanocapsules loaded with vitamin E (BPEA@VE NCs) could protect cells from both extracellular and intracellular damage by scavenging ROS. Simultaneously, the inflammatory reaction could also be downregulated, benefiting from the introduction of l-arginine. Furthermore, the biodegradation products of BPEA are natural metabolites of the body, such as amino acids and growth factors, guaranteeing the biocompatibility of the BPEA@VE NCs. The protective ability of the BPEA@VE NCs was also investigated in vivo for accelerated wound healing. All the results indicate that the BPEA@VE NCs have promising potential for the modulation of the local microenvironment in tissue engineering for excellent antioxidative and anti-inflammatory properties.

Advances of proteomics technologies for multidrug-resistant mechanisms.

Multidrug resistance (MDR) is a vital issue in cancer treatment. Drug resistance can be developed through a variety of mechanisms, including increased drug efflux, activation of detoxifying systems and DNA repair mechanisms, and escape of drug-induced apoptosis. Identifying the exact mechanism related in a particular case is a difficult task. Proteomics is the large-scale study of proteins, particularly their expression, structures and functions. In recent years, comparative proteomic methods have been performed to analyze MDR mechanisms in drug-selected model cancer cell lines. In this paper, we review the recent developments and progresses by comparative proteomic approaches to identify potential MDR mechanisms in drug-selected model cancer cell lines, which may help understand and design chemical sensitizers.

Natural Polymer-Based Hydrogels with Enhanced Mechanical Performances: Preparation, Structure, and Property.

Hydrogels based on natural polymers have bright application prospects in biomedical fields due to their outstanding biocompatibility and biodegradability. However, the poor mechanical performances of pure natural polymer-based hydrogels greatly limit their application prospects. Recently, a variety of strategies has been applied to prepare natural polymer-based hydrogels with enhanced mechanical properties, which generally exhibit stiffening, strengthening, and stretchable behaviors. This article summarizes the recent progress of natural polymer-based hydrogels with enhanced mechanical properties. From a structure point of view, four kinds of hydrogel are reviewed; double network hydrogels, nanocomposite hydrogels, click chemistry-based hydrogels, and supramolecular hydrogels. For each typical hydrogel, its preparation, structure, and mechanical performance are introduced in detail. At the end of this article, the current challenges and future prospects of hydrogels based on natural polymers are discussed and it is pointed out that 3D printing may offer a new platform for the development of natural polymer-based hydrogels.

Polydopamine/puerarin nanoparticle-incorporated hybrid hydrogels for enhanced wound healing.

Oxidative damage generated by various biochemical pathways can disrupt the oxidant/antioxidant balance in cells, causing slow wound healing and tissue regeneration; in this regard, a hydrogel dressing with antioxidant properties can promote wound healing; however, its design is still a challenge. Herein, a polydopamine/puerarin (PDA/PUE) nanoparticle-incorporated polyethylene glycol diacrylate hybrid hydrogel (PEG-DA/PDA/PUE) with antioxidant properties was prepared and used as a wound-healing material. Experimental observations indicated that the PEG-DA/PDA/PUE hydrogel possessed excellent swelling capacity and mechanical property. Moreover, the antioxidant capability was enhanced with an increase in the concentration of polydopamine/puerarin nanoparticles in the hydrogel. The hydrogel presented good cell proliferation and antioxidant activity, including a decrease in ROS and increase in the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity under oxidative stress conditions. Furthermore, the full-thickness skin-defect-regeneration process could be accelerated via the antioxidant hydrogel treatment. This study validated the potential applications of an antioxidant hydrogel for wound healing.

Development of Arg-Based Biodegradable Poly(ester urea) Urethanes and Its Biomedical Application for Bone Repair.

Thermal plastic polyurethanes (TPUs), serving as biomaterials, have become increasingly prevalent over time in many fields including artificial blood vessels, pericardial patches and other tissue engineering scaffolds by virtue of well adjustable performance. However, synthetic polyurethanes are, to some extent, inadequate for their cytocompatibility and biological activity owing to high hydrophobicity and lack of active groups. In this study, an amino-terminated bis(L-arginine) alkylene diester extender (L-Arg-8) was synthesized and Arg-based biodegradable poly(ester urea) urethanes (PEUUs) with different content of arginine groups were designed, synthesized and characterized in regard to the amelioration of the biodegradability, hydrophilicity and cytocompatibility of thermoplastic polyurethanes (TPUs) with PCL as soft segments. Biodegradability, hydrophilicity and positive surface charges increased after Arginine was introduced. As cytocompatibility was improved, PEUU materials A8-1.2 and A8-1.6 were proved to be suitable for human dental pulp stem cells (hDPSCs) to adhere, grow and proliferate on in vitro. These materials would unlock great potential for the use in tissue engineering and regeneration. Additionally, halloysite nanotubes (HNTs) were composited to PEUUs for further exploration to the applications in bone tissue. The addition of halloysite nanotubes further stimulated the osteogenic differentiation of human dental pulp stem cells in vitro. At the same time, a rat cranial defect model was built to assess effects of repair in vivo. Osteointegration and repair were promoted by patch-implanted groups. A8-1.2 6% HNTs showed the best repair. All the results indicated that Arg-based poly(ester urea) urethanes and the composites were conductive to bone repair.

Tofu-Based Hybrid Hydrogels with Antioxidant and Low Immunogenicity Activity for Enhanced Wound Healing.

Free radicals and inflammation in the skin suffering from trauma cause oxidative damage and delayed healing, leading to adverse wound conditions. To adequately investigate the effects of free radicals and controlled immunogenicity for wound healing, we propose a tofu-based hybrid hydrogel with antioxidant and low immunogenicity properties that can be used for wound healing. Tofu, a food source material, was introduced for the first time into gelatin methacryloyl (GelMA) hydrogels by the photo-crosslinking method. The results demonstrated that the incorporation of tofu influenced the pores, swelling, water vapor transmission and compressive properties of hydrogels greatly. The antioxidant activities of hydrogels had been enhanced with increasing rations of tofu, and the fibroblast culture showed good proliferation on the hybrid hydrogels, as well as slight immunogenicity, thereby inducing the M2 differentiation of macrophages. Further, a full-thickness skin wound model was created to study the healing effect of hybrid hydrogels. In vivo results confirmed that the antioxidant activity and slight immunological stimulation properties of tofu hydrogels could accelerate the wound healing rate and improve the skin tissue regeneration effect. The present study validates that the tofu-based hybrid hydrogels have multiple bioactivities and could be potential antioxidant and immunoregulation hydrogels in wound healing applications.

Double-Layer Microsphere Incorporated with Strontium Doped Calcium Polyphosphate Scaffold for Bone Regeneration.

To design and prepare a novel controlled release system for sustained release of two drugs. In this study, a double-layer microsphere was incorporated with strontium-doped calcium polyphosphate (SCPP) scaffold to facilitate bone regeneration and achieve skull repair. The double-layer microsphere combining tetracycline loaded sodium alginate and matrix metalloproteinase-2 (MMP-2) loaded chitosan was manufactured by electrospinning, which were further adhered to SCPP scaffold. The characteristics of microstructure were observed through scanning electron microscope. Loading efficiencies and the optimal ratio of microsphere of the obtained controlled release system were investigated. In addition, the cytotoxicity and the effects on osteoblast proliferation and expressions of osteogenesis-related factors were examined in vitro. Thereafter, the compound material with the controlled release system was implanted in the skull defect of rabbit to evaluate its properties of promoting bone regeneration. The results indicated that this novel controlled release system with SCPP scaffold and the double-layer microspheres loaded with tetracycline and MMP-2 could be a promising material for bones repair.

A quantitative comparable study on multi-hierarchy conformation of acid and pepsin-solubilized collagens from the skin of grass carp (Ctenopharyngodon idella).

This work aimed to improve yield of collagen from the grass carp skin by employing different strategies (acid-acid method, pepsin-pepsin method and acid-pepsin method, denoted as A-A, P-P, A-P, respectively). And further to conduct quantitative characterization on structural properties, self-assembly kinetics and gelation properties of these collagens. Herein, a two-step collagen extraction method (pepsin-pepsin) was established with the high yield. Meanwhile, structural measurements of high-yield collagen (pepsin-soluble collagen, PSC) and acid-soluble collagen (ASC) indicated that both collagens maintained the typical triple helical conformation of collagen type I. Moreover, the fibrillogenesis tests of PSC and ASC at the various temperatures confirmed that self-assembly were the entropy-driven process. The gelation time of both ASC and PSC was determined by the dynamic time sweep at the different frequencies combined with Winter's criterion. The self-assembly kinetics results showed that fibrillogenesis rate for ASC solution was faster, and more liable to gelation relative to PSC. Mechanical measurements suggested that ASC showed the more resistance ability to deformation than PSC due to more complicated architecture, confirmed by higher fractal dimension. However, the equivalent typical assemblies of PSC to ASC at the various stages can still be expected via controlling incubation time or temperature under the guidance of Arrhenius equation. This study would provide some strategies for achieving maximum utilization of waste biomass and significant insights into the mechanisms underlying the quantitative differences in multiple hierarchy conformation (molecule, fibrillogenesis and hydrogel) of ASC and PSC, which may benefit for subsequent design, development and optimization of collagen-based hydrogels in biomedical industries.

Gelatin methacryloyl (GelMA)-based biomaterials for bone regeneration.

Gelatin methacryloyl (GelMA)-based biomaterials have been widely used in various biomedical applications due to their suitable biological properties and tuneable physical characteristics. In particular, GelMA can be used as a versatile matrix for bone tissue engineering scaffolds via various strategies to overcome major obstacles such as insufficient mechanical property and uncontrollable degradation. This review presents the research status of GelMA, its structure and function, GelMA-based biomaterials and the development of methods along with their existing challenges.

Enhanced Osteoconductivity and Osseointegration in Calcium Polyphosphate Bioceramic Scaffold via Lithium Doping for Bone Regeneration.

Calcium polyphosphate (CPP) is a novel bioceramic bone substitute, which is favored because its composition is highly similar to natural bone. According to previous studies, doping ions into CPP is an effective and convenient method for overcoming the shortcomings, such as poor osteoconductivity of CPP. Lithium (Li) is a fairly new additive to bone substitutes that brought attention due to its role in osteogenesis. The present study was conducted to assess whether doping Li into CPP could influence the microstructure, degradation, and osteoinductivity of CPP. The results found that both CPP and Li-doped CPP (LiCPP) had a single beta-CPP phase, indicating that Li did not affect the crystallized phase. SEM images revealed that both scaffolds were porous, while the surface of LiCPP was rougher and more uneven compared to CPP. Also, a better degradation property of LiCPP was observed via weight loss and ion release tests. In vitro study found that LiCPP extracts had advantages of promoting osteoblasts' proliferation and differentiation over CPP extracts. In vivo study on rabbit's cranial defects was also conducted. Microcomputed tomography and histological staining showed that LiCPP had better osteoconductivity than CPP. This study proved that doping Li into CPP is a feasible modification method, and LiCPP might be a suitable bioceramic for bone tissue engineering.

Multi-Layered Hydrogels for Biomedical Applications.

Multi-layered hydrogels with organization of various functional layers have been the materials of choice for biomedical applications. This review summarized the recent progress of multi-layered hydrogels according to their preparation methods: layer-by-layer self-assembly technology, step-wise technique, photo-polymerization technique and sequential electrospinning technique. In addition, their morphology and biomedical applications were also introduced. At the end of this review, we discussed the current challenges to the development of multi-layered hydrogels and pointed out that 3D printing may provide a new platform for the design of multi-layered hydrogels and expand their applications in the biomedical field.

H2O2-Responsive Nanoparticle Based on the Supramolecular Self-Assemble of Cyclodextrin.

Designing stimuli responsive, controllable and biocompatible multifunctional nanoparticles is an important progress in the current quest for drug delivery systems. Herein, we devoted to developing a ß-cyclodextrin (ß-CD) based drug delivery nanoparticles (NPs) that release Bovine serum albumin (BSA) via glucose-responsive gate. The design involves synthesis of sodium alginate with ß-CD modified (Alg-ß-CD) and methoxypolyethylene glycol (mPEG-Fc) containing ferrocene (Fc) uncharged end-capping. When α-cyclodextrin (α-CD) was added with these two segments, the stable non-covalent supramolecular structure of Alg-ß-CD/mPEG-Fc/α-CD can be self-assembled into NPs in aqueous solution. BSA loaded Alg-ß-CD/mPEG-Fc/α-CD also has been prepared. Interestingly, these supramolecular Alg-ß-CD/mPEG-Fc/α-CD/BSA NPs showed uniform sphere structure and constant BSA loading content. Also, this new kind of NPs can disassemble in the present of hydrogen peroxide (H2O2). Since glucose oxidase (GOD) can oxidize glucose and produce H2O2, so this kind of polymeric NPs can also have glucose responsive behavior in the GOD containing environment. Developed functional Alg-ß-CD/mPEG-Fc/α-CD might be a promising drug delivery strategy for diabetes or immunotherapy with more efficiency.

Fabrication and characterization of a novel collagen-catechol hydrogel.

3,4-Dihydroxybenzaldehyde, a derivative of catechol and an agent with an extensive pharmacological and biological activities, was used to modify collagen and prepared hydrogels. The aldehyde group of 3,4-dihydroxybenzaldehyde interacted with the ɛ-amino group of collagen, and then the catechol group of 3,4-dihydroxybenzaldehyde was oxidized and self-polymerized. The chemical network formed due to the cross-linking bridges of polymerized catechol groups among collagen molecules, resulting in the transformation from solution to hydrogel. The results of the Fourier-transform infrared measurement indicated that the triple helix structure of collagen was integrated after cross-linking. The appearance of hydrogels changed from golden to dark brown with the increasing 3,4-dihydroxybenzaldehyde dose. When the weight ratio of 3,4-dihydroxybenzaldehyde and collagen increased from 0 to 2:1, the thermal denaturation temperature of collagen increased from 40.2 to 77.6℃ while the elastic modulus of collagen increased from 13.6 to 1061.4 Pa. The addition of 3,4-dihydroxybenzaldehyde also caused more compact morphologies and a dramatic enhancement in the enzymatic resistance of hydrogels. Moreover, the results of cell proliferation assay demonstrated the favorable biocompatibility of collagen hydrogels with 3,4-dihydroxybenzaldehyde. These promising data indicate that the novel hydrogels had significant potential for applications.

Self-assembly of collagen-based biomaterials: preparation, characterizations and biomedical applications.

The desired mechanical and biological performances of collagen that have led to its broad application as a building block in the biomedical field attributed to its intrinsic hierarchical structure from the nanoscale to macroscale, are discussed herein. Modulating the self-assembly process using regulatory factors can lead to obtaining collagenous materials with tuneable functional performance, which can then determine distinctive cellular responses. Herein, we present an overview of the corresponding characterization techniques used to detect the changes in light transmittance, architecture and mechanics during collagen fibrillogenesis. By combining regulatory parameters with characterization methods, researchers can selectively fabricate collagenous biomaterials with various functional responses.

A Tri-Stimuli-Responsive Shape-Memory Material Using Host-Guest Interactions as Molecular Switches.

A thermo-, photo- and chemoresponsive shape-memory material is successfully prepared by introducing α-cyclodextrin (αCD) and azobenzene (Azo) into a poly(acrylate acid)/alginate (PAA/Alg) network. The tri-stimuli-responsive formation/dissociation of αCD-Azo acts as molecular switches freezing or increasing the molecular mobility. The resulting film herein can be processed into temporary shapes as needed and recovers its initial shape upon the application of light irradiation, heating, or chemical agent independently. Furthermore, the agar diffusion test suggests that the α-CD-Alg/Azo-PAA has good biocompatibility for L929 fibroblast-like cells.

pH-Switchable macroscopic assembly through host-guest inclusion.

A novel pH-switchable macroscopic assembly is reported using alginate-based hydrogels functionalized with host (α-cyclodextrin, αCD) and guest (diethylenetriamine, DETA) moieties. Since the interaction of αCD and DETA is pH sensitive, the host hydrogel and guest hydrogel could adhere together when the pH is 11.5 and separate when the pH is 7.0. Furthermore, this pH-controlled adhesion and dissociation shows a good reversibility. The host and guest polymers have good biocompatibility; therefore, this pH-sensitive macroscopic assembly shows great potential in biotechnological and biomedical applications.

Redox- and glucose-induced shape-memory polymers.

A novel redox-induced shape-memory polymer (SMP) is prepared by crosslinking ß-cyclodextrin modified chitosan (ß-CD-CS) and ferrocene modified branched ethylene imine polymer (Fc-PEI). The resulting ß-CD-CS/Fc-PEI contains two crosslinks: reversible redox-sensitive ß-CD-Fc inclusion complexes serving as reversible phases, and covalent crosslinks serving as fixing phases. It is shown that this material can be processed into temporary shapes as needed in the reduced state and recovers its initial shape after oxidation. The recovery ratio and the fixity ratio are both above 70%. Furthermore, after entrapping glucose oxidase (GOD) in the system, the material shows a shape memory effect in response to glucose. The recovery ratio and the fixity ratio are also above 70%.