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Diabetic foot ulcers often become infected, leading to treatment complications and increased risk of loss of limb. Therapeutics to manage infection and simultaneously promote healing are needed. Here we report on the development of a Janus liposozyme that treats infections and promotes wound closure and re-epithelialization. The Janus liposozyme consists of liposome-like selenoenzymes for reactive oxygen species (ROS) scavenging to restore tissue redox and immune homeostasis. The liposozymes are used to encapsulate photosensitizers for photodynamic therapy of infections. We demonstrate application in methicillin-resistant Staphylococcus aureus -infected diabetic wounds showing high ROS levels for antibacterial function from the photosensitizer and nanozyme ROS scavenging from the liposozyme to restore redox and immune homeostasis. We demonstrate that the liposozyme can directly regulate macrophage polarization and induce a pro-regenerative response. By employing single-cell RNA sequencing, T cell-deficient Rag1 −/− mice and skin-infiltrated immune cell analysis, we further reveal that IL-17-producing γδ T cells are critical for mediating M1/M2 macrophage transition. Manipulating the local immune homeostasis using the liposozyme is shown to be effective for skin wound repair and tissue regeneration in mice and mini pigs. Therapies for treating bacterial infection and increasing wound healing are needed. Here the authors report a liposozyme that combines reactive oxygen species generation and scavenging for antibacterial action and modulation of redox and immune homeostasis, increasing wound healing.

Constructing nanomaterials mimicking the coordination environments of natural enzymes may achieve biomimetic catalysis. Here we construct a two-dimensional (2D) metal-organic framework (MOF) nanosheet catalyst as an artificial antioxidase for nanocatalytic rheumatoid arthritis treatment. The 2D MOF periodically assembles numbers of manganese porphyrin molecules, which has a metal coordination geometry analogous to those of two typical antioxidases, human mitochondrial manganese superoxide dismutase (Mn-SOD) and human erythrocyte catalase. The zinc atoms of the 2D MOF regulate the metal-centered redox potential of coordinated manganese porphyrin ligand, endowing the nanosheet with both SOD- and catalase-like activities. Cellular experiments show unique anti-inflammatory and pro-biomineralization performances of the 2D MOF, while in vivo animal model further demonstrates its desirable antiarthritic efficacy. It is expected that such a nanocatalytic antioxidation concept may provide feasible approaches to future anti-inflammatory treatments. Inflammatory diseases such as rheumatoid arthritis are associated with high reactive oxygen species levels. Here, the authors report on 2D metal-organic frameworks as an artificial antioxidase with the same manganese coordination centre as two natural enzymes, and demonstrate their anti-inflammatory effects and anti-arthritic effects in vivo.

The past 20 years have witnessed ever- growing evidence that the mechanical properties of biological tissues, from nanoscale to macroscale dimensions, are fundamental for cellular behaviour and consequent tissue functionality. This knowledge, combined with previously known biochemical cues, has greatly advanced the field of biomaterial development, tissue engineering and regenerative medicine. It is now established that approaches to engineer biological tissues must integrate and approximate the mechanics, both static and dynamic, of native tissues. Nevertheless, the literature on the mechanical properties of biological tissues differs greatly in methodology, and the available data are widely dispersed. This Review gathers together the most important data on the stiffness of living tissues and discusses the intricacies of tissue stiffness from a materials perspective, highlighting the main challenges associated with engineering lifelike tissues and proposing a unified view of this as yet unreported topic. Emerging advances that might pave the way for the next decadeâ s take on bioengineered tissue stiffness are also presented, and differences and similarities between tissues in health and disease are discussed, along with various techniques for characterizing tissue stiffness at various dimensions from individual cells to organs.

Delivery technologies for the CRISPR-Cas9 (CRISPR, clustered regularly interspaced short palindromic repeats) gene editing system often require viral vectors, which pose safety concerns for therapeutic genome editing1. Alternatively, cationic liposomal components or polymers can be used to encapsulate multiple CRISPR components into large particles (typically >100 nm diameter); however, such systems are limited by variability in the loading of the cargo. Here, we report the design of customizable synthetic nanoparticles for the delivery of Cas9 nuclease and a single-guide RNA (sgRNA) that enables the controlled stoichiometry of CRISPR components and limits the possible safety concerns in vivo. We describe the synthesis of a thin glutathione (GSH)-cleavable covalently crosslinked polymer coating, called a nanocapsule (NC), around a preassembled ribonucleoprotein (RNP) complex between a Cas9 nuclease and an sgRNA. The NC is synthesized by in situ polymerization, has a hydrodynamic diameter of 25 nm and can be customized via facile surface modification. NCs efficiently generate targeted gene edits in vitro without any apparent cytotoxicity. Furthermore, NCs produce robust gene editing in vivo in murine retinal pigment epithelium (RPE) tissue and skeletal muscle after local administration. This customizable NC nanoplatform efficiently delivers CRISPR RNP complexes for in vitro and in vivo somatic gene editing.

Achieving rapid and scar-free wound repair is a key goal in the field of regenerative medicine. Herein, a dynamically Schiff base-crosslinked hydrogel (F/R gel) with phase-adaptive regulating functions is constructed to integratedly promote rapid re-epithelization with suppressed scars on chronic infected wounds. Specifically, the gel effectively eliminates multidrug-resistant bacterial biofilm at infection stage via antimicrobial activity of ε-polylysine firstly dissociated from hydrogel matrix in infectious microenvironment, and interrupts the severe oxidative stress-inflammation cycle at wound site by the released ceria nanozyme, thus stimulating a pro-regenerative environment to ensure tissue repair. Subsequently, fibroblast growth factor/ c-Jun siRNA co-loaded microcapsules gradually disintegrate to release drugs, facilitating neoangiogenesis and cell proliferation but simultaneously blocking c-Jun overexpression for fibrotic scar suppression. Notably, the F/R gel facilitates normal-like skin regeneration with no perceptible scars formed on infected male mouse wound and female rabbit ear wound models. Our work offers a promising regenerative strategy emphasizing immunomodulatory and fibroblast subtype modulation for scarless wound repair. It is challenging to achieve scar-free repair of chronic wounds as they often feature the occurrence of multiple healing phases in an unpredictable and nonlinear manner. Here, the authors report a healing phase-adaptive regulating hydrogel that exhibits hierarchically delivering performance for programmed modulation of chronic infected wounds.

Biological systems have evolved to utilize numerous proteins with capacity to bind polysaccharides for the purpose of optimizing their function. A well-known subset of these proteins with binding domains for the highly diverse sulfated polysaccharides are important growth factors involved in biological development and tissue repair. We report here on supramolecular sulfated glycopeptide nanostructures, which display a trisulfated monosaccharide on their surfaces and bind five critical proteins with different polysaccharide-binding domains. Binding does not disrupt the filamentous shape of the nanostructures or their internal β-sheet backbone, but must involve accessible adaptive configurations to interact with such different proteins. The glycopeptide nanostructures amplified signalling of bone morphogenetic protein 2 significantly more than the natural sulfated polysaccharide heparin, and promoted regeneration of bone in the spine with a protein dose that is 100-fold lower than that required in the animal model. These highly bioactive nanostructures may enable many therapies in the future involving proteins. Highly bioactive supramolecular nanostructures displaying sulfated glycopeptides on their surfaces were designed in order to mimic the polysaccharides that bind and activate a plethora of proteins in mammalian biology during development and tissue regeneration.

In tissue engineering and regenerative medicine, a biomaterial provides mechanical support and biochemical signals to encourage cell attachment and modulate cell behaviour. Nature’s template for a biomaterial is the extracellular matrix (ECM). The ECM contains intrinsic biochemical and mechanical cues that regulate cell phenotype and function in development, in homeostasis and in response to injury. The use of ECM-based materials in biomedical research has advanced from coating cell culture plates with purified ECM components to the design of ECM-mimicking biomaterials and the engineering of decellularized tissues aimed at recapitulating the dynamics, composition and structure of the ECM. In this Review, we highlight important matrix properties and functions in the context of tissue engineering and regenerative medicine, consider techniques such as proteomics for the investigation of matrix structure and composition and discuss different engineering strategies for the design of matrix-mimicking biomaterials. Tissue, whole organ and cell culture decellularization approaches are examined for their potential to preserve the tissue-specific biochemical composition and ultrastructure of the ECM and for the development of biomaterials that promote the formation of functional tissues in clinical applications. Finally, we investigate challenges and opportunities of ECM biomaterials for the design of organotypic models to study disease progression, for the ex vivo creation of engineered tissue and for the clinical translation of functional tissue reconstruction strategies in vivo. The extracellular matrix is nature’s template for an ideal biomaterial to guide tissue homeostasis and repair. In this Review, matrix-mimicking biomaterials and decellularized matrices are discussed for their potential to reconstruct and repair tissues in vitro and in vivo.

The controlled delivery of nucleic acids to selected tissues remains an inefficient process mired by low transfection efficacy, poor scalability because of varying efficiency with cell type and location, and questionable safety as a result of toxicity issues arising from the typical materials and procedures employed. High efficiency and minimal toxicity in vitro has been shown for intracellular delivery of nuclei acids by using nanoneedles, yet extending these characteristics to in vivo delivery has been difficult, as current interfacing strategies rely on complex equipment or active cell internalization through prolonged interfacing. Here, we show that a tunable array of biodegradable nanoneedles fabricated by metal-assisted chemical etching of silicon can access the cytosol to co-deliver DNA and siRNA with an efficiency greater than 90%, and that in vivo the nanoneedles transfect the VEGF-165 gene, inducing sustained neovascularization and a localized sixfold increase in blood perfusion in a target region of the muscle. Efficient in vivo cytosolic delivery of nucleic acids through cell-membrane puncturing by an array of biodegradable silicon nanoneedles induces sustained local neovascularization in muscle.

Organs are complex systems composed of different cells, proteins and signalling molecules that are arranged in a highly ordered structure to orchestrate a myriad of functions in our body. Biofabrication strategies can be applied to engineer 3D tissue models in vitro by mimicking the structure and function of native tissue through the precise deposition and assembly of materials and cells. This approach allows the spatiotemporal control over cell–cell and cell–extracellular matrix communication and thus the recreation of tissue-like structures. In this Review, we examine biofabrication strategies for the construction of functional tissue replacements and organ models, focusing on the development of biomaterials, such as supramolecular and photosensitive materials, that can be processed using biofabrication techniques. We highlight bioprinted and bioassembled tissue models and survey biofabrication techniques for their potential to recreate complex tissue properties, such as shape, vasculature and specific functionalities. Finally, we discuss challenges, such as scalability and the foreign body response, and opportunities in the field and provide an outlook to the future of biofabrication in regenerative medicine. Biofabrication can be applied to replicate tissues and organs for regenerative medicine and for the creation of 3D in vitro tissue models. In this Review, the recent advances in biomaterials and biofabrication technologies are discussed, and challenges and opportunities are highlighted.

Despite the wide applications, systematic mechanobiological investigation of 3D porous scaffolds has yet to be performed due to the lack of methodologies for decoupling the complex interplay between structural and mechanical properties. Here, we discover the regulatory effect of cryoprotectants on ice crystal growth and use this property to realize separate control of the scaffold pore size and stiffness. Fibroblasts and macrophages are sensitive to both structural and mechanical properties of the gelatin scaffolds, particularly to pore sizes. Interestingly, macrophages within smaller and softer pores exhibit pro-inflammatory phenotype, whereas anti-inflammatory phenotype is induced by larger and stiffer pores. The structure-regulated cellular mechano-responsiveness is attributed to the physical confinement caused by pores or osmotic pressure. Finally, in vivo stimulation of endogenous fibroblasts and macrophages by implanted scaffolds produce mechano-responses similar to the corresponding cells in vitro, indicating that the physical properties of scaffolds can be leveraged to modulate tissue regeneration. Cellular responses to mechanical stimulation have emerged as an important area of research. Here, the authors use cryoprotectant to control the pore size and mechanical properties of porous scaffolds without changing the scaffold composition to allow for the study of cellular mechano-responsiveness in 3D.