Senescence-Targeted and NAD+-Dependent SIRT1-Activated Nanoplatform to Counteract Stem Cell Senescence for Promoting Aged Bone Regeneration.

Age-related bone defects are a leading cause of disability and mortality in elderly individuals, and targeted therapy to delay the senescence of bone marrow-derived mesenchymal stem cells (MSCs) has emerged as a promising strategy to rejuvenate bone regeneration in aged scenarios. More specifically, activating the nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) pathway is demonstrated to effectively counteract MSC senescence and thus promote osteogenesis. Herein, based on an inventively identified senescent MSC-specific surface marker Kremen1, a senescence-targeted and NAD+ dependent SIRT1 activated nanoplatform is fabricated with a dual delivery of resveratrol (RSV) (SIRT1 promoter) and nicotinamide riboside (NR, NAD+ precursor). This targeting nanoplatform exhibits a strong affinity for senescent MSCs through conjugation with anti-Kremen1 antibodies and enables specifically responsive release of NR and RSV in lysosomes via senescence-associated ß-galactosidase-stimulated enzymatic hydrolysis of the hydrophilic chain. Furthermore, this nanoplatform performs well in promoting aged bone formation both in vitro and in vivo by boosting NAD+, activating SIRT1, and delaying MSC senescence. For the first time, a novel senescent MSC-specific surface marker is identified and aged bone repair is rejuvenated by delaying senescence of MSCs using an active targeting platform. This discovery opens up new insights for nanotherapeutics aimed at age-related diseases.

Non-Pore Dependent and MMP-9 Responsive Gelatin/Silk Fibroin Composite Microparticles as Universal Delivery Platform for Inhaled Treatment of Lung Cancer.

Developing a drug delivery platform that possesses universal drug loading capacity to meet various requirements of cancer treatment is a challenging yet interesting task. Herein, a self-assembled gelatin/silk fibroin composite (GSC) particle based drug delivery system is developed via microphase separation followed by desolvation process. Thanks to its preassembled microphase stage, this GSC system is suitable for varying types of drugs. The desolvation process fix drugs inside GSC rapidly and densify the GSC structure, thereby achieving efficient drug loading and providing comprehensive protection for loaded drugs. Actually, the size of this brand-new non-pore dependent drug delivery system can be easily adjusted from 100 nm to 20 µm to fit different scenarios. This work selects GSC with 3 µm diameter as the universal inhaled drug delivery platform, which shows an excellent transmucosal penetration and lung retention ability. Additionally, the MMP-9 sensitive degradation property of GSC enhances the targeted efficiency of drugs and reduces side effects. Intestinally, GSC can self-amplify the regulation of innate immunity to reverse the cancerous microenvironment into an antitumor niche, significantly improving the therapeutic effect of drugs. This study of GSC universal drug platform provides a new direction to develop the next-generation of drug delivery system for lung cancer.

Repurpose dasatinib and quercetin: Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration.

Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis (PMO) and related diseases, such as bone degeneration, show multiple adverse effects nowadays. Targeting senescent cells (SnCs) and the consequent senescence-associated secretory phenotype (SASP) with a combination of dasatinib and quercetin (DQ) is a recently developed novel therapy for multiple age-related diseases. Herein, we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation, especially senescent mesenchymal stem cells (MSCs) characterized by exhaustion and dysfunction in middle aged rats. Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function. Local administration of DQ and bone morphogenetic protein 2 (BMP2) in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration. Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.

A biomimetic and bioactive scaffold with intelligently pulsatile teriparatide delivery for local and systemic osteoporosis regeneration.

Osteoporosis is one of the most disabling consequences of aging, osteoporotic fractures and higher risk of the subsequent fractures leading to substantial disability and deaths, indicating both local fractures healing and the early anti-osteoporosis therapy are of great significance. Teriparatide is strong bone formation promoter effective in treating osteoporosis, while side effects limit clinical applications. Traditional drug delivery is lack of sensitive and short-term release, finding a new non-invasive and easily controllable drug delivery to not only repair the local fractures but also improve total bone mass has remained a great challenge. Thus, bioinspired by the natural bone components, we develop appropriate interactions between inorganic biological scaffolds and organic drug molecules, achieving both loaded with the teriparatide in the scaffold and capable of releasing on demand. Herein, biomimetic bone microstructure of mesoporous bioglass, a near-infrared ray triggered switch, thermosensitive liposomes based on a valve, and polydopamine coated as a heater is developed rationally for osteoporotic bone regeneration. Teriparatide is pulsatile released from intelligent delivery, not only rejuvenating osteoporotic bone defect, but also presenting strong systemic anti-osteoporosis therapy. This biomimetic bone carrying novel drug delivery platform is well worth expecting to be a new promising strategy and clinically commercialized to help patients survive from the osteoporotic fracture.

Tough, Flexible, and Bioactive Amphoteric Copolymer-Based Hydrogel for Bone Regeneration without Encapsulation of Seed Cells/Simulating Cues.

Bone tissue scaffolds with good bulk or surface osteoconductivity are always pursued by biomaterial scientists. In this paper, we design a tough and flexible amphoteric copolymer-based (AC) hydrogel with bioactive groups for bone regeneration. In detail, our hydrogels are copolymerized with N-acyl glycinamide (NAGA), anionic acrylate alendronate (AcAln), and cationic (2-(acryloyloxy)ethyl) trimethyl ammonium chloride (DMAEA-Q) by free radical polymerization. There are three kinds of synergetic physical cross-links among our polyamphion hydrogels: (1) double hydrogen bonds between amide groups in NAGA to provide toughness, (2) hydrogen bonds between dual bisphosphite groups in AcAln, and (3) weak ionic pairs between the anionic bisphosphite groups and the cationic quaternary ammonium groups in DMAEA-Q to offer flexibility. The AC hydrogel shows osteoid-like viscoelasticity, which makes the AC hydrogel osteogenesis inductive. During the repairing process, the bioactive bisphosphite groups accelerate the calcium fixation to expedite the mineralization of the new-formed bone. At the same time, the surface charge property of AC hydrogels also prevents fibrous cyst formation, thus guaranteeing osseointegration. Our in vitro data strongly demonstrate that the AC hydrogel is an excellent matrix to induce osteogenesis of rat bone marrow mesenchymal stem cells. More importantly, the following in vivo experiments further prove that the AC hydrogel can reach satisfactory bone regeneration without encapsulation of seed cells or application of external simulating cues. These exciting results demonstrate that our AC hydrogel is a promising scaffold for bone regeneration. Our work can also inspire the constituent and structure design of biomaterial scaffolds for tissue regeneration.

Ionic interaction-driven switchable bactericidal surfaces.

Bacteria in the external environment inevitably invade the wound and subsequently colonize the wound surface during surgery and biomedical operations, which slows down the process of wound healing and tissue repair; this poses a significant threat to human health. Therefore, the development of an intelligent antibacterial surface has become the focus of research in the field of antimicrobial strategies, which has important social and economic significance. Here, we present a simple approach of producing an ionic interaction-driven anionic activation substratum which is then functionalized with cationic molecules through coulombic interactional immobilization. The switchable multifunctional antibacterial surface can decrease bacterial attachment and inactivate the attached microorganisms, thus overcoming the conventional challenge for antibacterial surfaces. Briefly, poly (3-sulfopropyl methacrylate potassium salt) (PSPMA) brushes were constructed by surface-initiated atom transfer radical polymerization on silicon or cotton fabric substrates, and a positive-charged component, namely lysozyme (LYZ), hexadecyl trimethyl ammonium bromide (CTAB) or chitosan (CS), was loaded on negative-charged sulfonate groups through electrostatic interactions. The resultant brush-grafted surfaces exhibited more than ∼95.5% bactericidal efficacy and ∼92.8% release rate after the introduction of an adequate amount of contra-ions (1.0 M; Na+ & Cl-) against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus, thus achieving a regenerated surface through the cyclic process of "assembly-dissociation". Smart cotton fabric (Fabric-PSPMA/LYZ and Fabric-PSPMA/CS) surfaces were constructed, which were found to promote wound epidermal tissue regeneration with a higher efficiency after 7-day in vivo studies. This ionic interaction-driven method used in the present work is simple and can reversibly renew antibacterial surfaces, which will help in the wider utilization of switchable antibacterial materials with a more ecologic and economic significance. STATEMENT OF SIGNIFICANCE: Smart antibacterial surfaces with renewable characteristics have attracted considerable interests over the past few years. Here, we used ionic interaction-driven force to manipulate dynamic conformational changes in PSPMA surface brushes, accompanied by highly switchable bacteria killing and bacteria releasing behaviors. Different cationic molecules were also designed for assembly/dissociation on the PSPMA-modified surfaces, and the essential parameters, including chemical structures, molecular weight, and cationic charge density, were investigated. With the refined structural combinations and the balance of bacteria killing/bacteria releasing behaviors, smart cotton fabrics (e.g., Fabric-PSPMA/lysozyme and Fabric-PSPMA/chitosan) were designed that could promote wound healing and tissue repair. These results contribute to the fundamental understanding of a switchable cationic-anionic pair design and the corresponding practical, renewable, highly antibacterial fabric.

Versatile and Simple Strategy for Preparing Bilayer Hydrogels with Janus Characteristics.

Bilayer hydrogels are attracting tremendous attention for their capability to integrate several different functions on the two sides of the gel, that is, imparting the gel with Janus characteristics, which is highly desired in many engineering and biomedical applications including soft actuators, hydrogel patches, and wearable electronics. However, the preparation process of the bilayer materials usually involves several complicated steps and is time-consuming, while the interfacial bonding is another main concern. Here, a simple and versatile method is proposed to obtain bilayer hydrogels within just one step based on the method of introducing viscosity contrast of the precursors for different layers. The bilayer structure can be well maintained during the whole preparation process with a constrained interfacial molecular exchange to ensure the strong bonding strength. The key requirements for forming distinct bilayer structures in situ are studied and discussed in detail. Bilayer hydrogels with different chemical designs are prepared via this strategy to tailor the good distribution of desired functions for soft actuators, wound healing patches, and wearable electronics. We believe that the strategy illustrated here will provide new insights into the preparation and application of bilayer materials.

Cationic peptide-based salt-responsive antibacterial hydrogel dressings for wound healing.

Development of biological dressings has received widespread attentions due to their good breathability, biocompatibility, wettability, and the ability to absorb wound exudate without sticking to the wound. However, current proposed antibacterial hydrogels are limited antibacterial ability, short service life and insufficient biocompatibility, which are still challenging to address intricate practical applications. Here we develop a cationic peptide-based, salt-responsive hydrogel dressing with triple functions of antifouling, bactericidal, and bacterial release by combining ε-poly-l-lysine, poly(ethylene glycol) diglycidyl ether, and poly(DVBAPS-co-GMA) via a one-pot method. These designed hydrogels enabled to further quaternize to enhance antibacterial property due to the presence of amine residues. The resultant hydrogels present good antibacterial activity (>90%), biocompatibility, cell proliferation efficacy (~400%) and adhesiveness. Through in vivo and in vitro antibacterial capability tests, it is also found that hydrogels have good antifouling and sterilization capabilities, and the sterilization rate could reach up to ~96%. In addition, ~94% of the attached bacterial can be released after saline/water switching for several cycles. Taken together, the designed multiple antibacterial dressing prolongs the lifespan relying on reversible salt-responsive release and meet special requirements for wound healing. This work not only provides a platform to highlight its promising potentials in wound management but also gives a custom strategy to biomedical applications.

Retraction Notice to: Application of Inorganic Nanocomposite Hydrogels in Bone Tissue Engineering.

[This retracts the article DOI: 10.1016/j.isci.2020.101845.].

Host-Guest Interaction-Mediated Photo/Temperature Dual-Controlled Antibacterial Surfaces.

Development of smart switchable surfaces to solve the inevitable bacteria attachment and colonization has attracted much attention; however, it proves very challenging to achieve on-demand regeneration for noncontaminated surfaces. We herein report a smart, host-guest interaction-mediated photo/temperature dual-controlled antibacterial surface, topologically combining stimuli-responsive polymers with nanobactericide. From the point of view of long-chain polymer design, the peculiar hydration layer generated by hydrophilic poly(2-hydroxyethyl methacrylate) (polyHEMA) segments severs the route of initial bacterial attachment and subsequent proliferation, while the synergistic effect on chain conformation transformation poly(N-isopropylacrylamide) (polyNIPAM) and guest complex dissociation azobenzene/cyclodextrin (Azo/CD) complex greatly promotes the on-demand bacterial release in response to the switch of temperature and UV light. Therefore, the resulting surface exhibits triple successive antimicrobial functions simultaneously: (i) resists ∼84.9% of initial bacterial attachment, (ii) kills ∼93.2% of inevitable bacteria attack, and (iii) releases over 94.9% of killed bacteria even after three cycles. The detailed results not only present a potential and promising strategy to develop renewable antibacterial surfaces with successive antimicrobial functions but also contribute a new antimicrobial platform to biomedical or surgical applications.

Microsphere-Embedded Hydrogel Sustained-Release System to Inhibit Postoperative Epidural Fibrosis.

As a common complication of spine surgery, postoperative epidural fibrosis is an important cause of failed back surgery syndrome (FBSS), yet there is no effective clinical intervention to tackle it. Herein, for the first time, we develop a strategy of combining a gelatin methacryloyl (GelMA) hydrogel matrix with poly(lactic-co-glycolic acid) (PLGA) microsphere-encapsulated resveratrol (RSV), which aims to synergistically promote the inhibition effect on epidural fibrosis. The resultant RSV@PLGA-GelMA (8% w/v) hydrogels possess optimal mechanical properties and prompt the matrix sustainably and stably to release RSV for several weeks. It is further shown that the hybrid hydrogels without the drug exhibit good biosafety without distinct cytotoxicity, while RSV@PLGA-GelMA could prevent fibroblast proliferation and migration. Further rat laminectomy model indicates that the RSV@PLGA-GelMA hydrogels reduce epidural fibrosis by inhibiting fibroblast proliferation and extracellular matrix overexpression and deposition via a TGF-ß/Smad signaling pathway. Consequently, we believe that such a creative structural combination will be a promising strategy for preventing postoperative epidural fibrosis of spine surgery.

Application of Inorganic Nanocomposite Hydrogels in Bone Tissue Engineering.

Bone defects caused by trauma and surgery are common clinical problems encountered by orthopedic surgeons. Thus, a hard-textured, natural-like biomaterial that enables encapsulated cells to obtain the much-needed biophysical stimulation and produce functional bone tissue is needed. Incorporating nanomaterials into cell-laden hydrogels is a straightforward tactic for producing tissue engineering structures that integrate perfectly with the body and for tailoring the material characteristics of hydrogels without hindering nutrient exchange with the surroundings. In this review, recent developments in inorganic nanocomposite hydrogels for bone tissue engineering that are of vital importance but have not yet been comprehensively reviewed are summarized.