Electrospray Nano-Micro Composite Sodium Alginate Microspheres with Shape-Adaptive, Antibacterial, and Angiogenic Abilities for Infected Wound Healing.

Nonhealing infectious wounds, characterized by bacterial colonization, wound microenvironment destruction, and shape complexity, present an intractable problem in clinical practice. Inspired by LEGOs, building-block toys that can be assembled into desired shapes, we proposed the use of electrospray nano-micro composite sodium alginate (SA) microspheres with antibacterial and angiogenic properties to fill irregularly shaped wounds instantly. Specifically, porous poly(lactic-co-glycolic acid) (PLGA) microspheres (MSs) encapsulating basic fibroblast growth factor (bFGF) were produced by a water-in-oil-in-water double-emulsion method. Then, bFGF@MSs were blended with the SA solution containing ZIF-8 nanoparticles. The resultant solution was electrosprayed to obtain nano-micro composite microspheres (bFGF@MS/ZIF-8@SAMSs). The composite MSs' size could be regulated by PLGA MS mass proportion and electrospray voltage. Moreover, bFGF, a potent angiogenic agent, and ZIF-8, bactericidal nanoparticles, were found to release from bFGF@MS/ZIF-8@SAMSs in a controlled and sustainable manner, which promoted cell proliferation, migration, and tube formation and killed bacteria. Through experimentation on rat models, bFGF@MS/ZIF-8@SAMSs were revealed to adapt to wound shapes and accelerate infected wound healing because of the synergistic effects of antibacterial and angiogenic abilities. In summation, this study developed a feasible approach to prepare bioactive nano-micro MSs as building blocks that can fill irregularly shaped infected wounds and improve healing.

Molecular Engineering of Electrosprayed Hydrogel Microspheres to Achieve Synergistic Anti-Tumor Chemo-Immunotherapy with ACEA Cargo.

Molecular engineering of drug delivering platforms to provide collaborative biological effects with loaded drugs is of great medical significance. Herein, cannabinoid receptor 1 (CB1)- and reactive oxygen species (ROS)-targeting electrosprayed microspheres (MSs) are fabricated by loading with the CB1 agonist arachidonoyl 2'-chloroethylamide (ACEA) and producing ROS in a photoresponsive manner. The synergistic anti-tumor effects of ACEA and ROS released from the MSs are assessed. ACEA inhibits epidermal growth factor receptor signaling and altered tumor microenvironment (TME) by activating CB1 to induce tumor cell death. The MSs are composed of glycidyl methacrylate-conjugated xanthan gum (XGMA) and Fe3+, which form dual molecular networks based on a Fe3+-(COO-)3 network and a C═C addition reaction network. Interestingly, the Fe3+-(COO-)3 network can be disassembled instantly under the conditions of lactate sodium and ultraviolet exposure, and the disassembly is accompanied by massive ROS production, which directly injures tumor cells. Meanwhile, the transition of dual networks to a single network boosts the ACEA release. Together, the activities of the ACEA and MSs promote immunogenic tumor cell death and create a tumor-suppressive TME by increasing M1-like tumor-associated macrophages and CD8+ T cells. In summation, this study demonstrates strong prospects of improving anti-tumor effects of drug delivering platforms through molecular design.

Advancements in hydrogel-based drug delivery systems for the treatment of inflammatory bowel disease: a review.

Inflammatory bowel disease (IBD) is a chronic disorder that affects millions of individuals worldwide. However, current drug therapies for IBD are plagued by significant side effects, low efficacy, and poor patient compliance. Consequently, there is an urgent need for novel therapeutic approaches to alleviate IBD. Hydrogels, three-dimensional networks of hydrophilic polymers with the ability to swell and retain water, have emerged as promising materials for drug delivery in the treatment of IBD due to their biocompatibility, tunability, and responsiveness to various stimuli. In this review, we summarize recent advancements in hydrogel-based drug delivery systems for the treatment of IBD. We first identify three pathophysiological alterations that need to be addressed in the current treatment of IBD: damage to the intestinal mucosal barrier, dysbiosis of intestinal flora, and activation of inflammatory signaling pathways leading to disequilibrium within the intestines. Subsequently, we discuss in depth the processes required to prepare hydrogel drug delivery systems, from the selection of hydrogel materials, types of drugs to be loaded, methods of drug loading and drug release mechanisms to key points in the preparation of hydrogel drug delivery systems. Additionally, we highlight the progress and impact of the hydrogel-based drug delivery system in IBD treatment through regulation of physical barrier immune responses, promotion of mucosal repair, and improvement of gut microbiota. In conclusion, we analyze the challenges of hydrogel-based drug delivery systems in clinical applications for IBD treatment, and propose potential solutions from our perspective.

In situ bioprinting of double network anti-digestive xanthan gum derived hydrogel scaffolds for the treatment of enterocutaneous fistulas.

The clinical treatment of enterocutaneous fistula is challenging and causes significant patient discomfort. Fibrin gel can be used to seal tubular enterocutaneous fistulas, but it has low strength and poor digestion resistance. Based on in situ bioprinting and the anti-digestive properties of xanthan gum (XG), we used carboxymethyl chitosan (CMC) and xanthan gum modified by grafted glycidyl methacrylate (GMA) and aldehyde (GCX) as the ink to print a double network hydrogel that exhibited high strength and an excellent anti-digestive performance. In addition, in vitro studies confirmed the biocompatibility, degradability, and self-healing of hydrogels. In our rabbit tubular enterocutaneous fistula model, the in situ printed hydrogel resisted corrosion due to the intestinal fluid and acted as a scaffold for intestinal mucosal cells to proliferate on its surface. To summarize, in situ bioprinting GCX/CMC double network hydrogel can effectively block tubular enterocutaneous fistulas and provide a stable scaffold for intestinal mucosal regeneration.

Establishment and evaluation of an improved rat model of open abdomen.

INTRODUCTION: This study aimed to establish an animal model of open abdomen (OA) through temporary abdominal closure via different techniques. METHODS: Adult male Sprague-Dawley rats were randomly divided into three groups: group A (OA with polypropylene mesh alone); group B (OA with polypropylene mesh combined with a patch); and group C (OA with polypropylene mesh and a sutured patch). Vital signs, pathophysiological changes, and survival rates were closely monitored in the rats for 7 days after surgery. Abdominal X-rays and histopathological examinations were performed to assess abdominal organ changes and wound healing. RESULTS: The results showed no significant difference in mortality rates among the three groups (p > 0.05). However, rats in group B exhibited superior overall condition, cleaner wounds, and a higher rate of wound healing compared to the other groups (p < 0.05). Abdominal X-rays indicated that varying degrees of distal intestinal obstruction in all groups. Histopathological examinations revealed fibrous hyperplasia, inflammatory cell infiltration, neovascularization, and collagen deposition in all groups. Group B demonstrated enhanced granulation tissue generation, neovascularization, and collagen deposition compared to the other groups (p < 0.05). CONCLUSIONS: Polypropylene mesh combined with patches is the most suitable method for establishing an animal model of OA. This model successfully replicated the pathological and physiological changes in postoperative patients with OA, specifically the progress of abdominal skin wound healing. It provides a practical and reliable animal model for OA research.

A click chemistry-mediated all-peptide cell printing hydrogel platform for diabetic wound healing.

High glucose-induced vascular endothelial injury is a major pathological factor involved in non-healing diabetic wounds. To interrupt this pathological process, we design an all-peptide printable hydrogel platform based on highly efficient and precise one-step click chemistry of thiolated γ-polyglutamic acid, glycidyl methacrylate-conjugated γ-polyglutamic acid, and thiolated arginine-glycine-aspartate sequences. Vascular endothelial growth factor 165-overexpressed human umbilical vein endothelial cells are printed using this platform, hence fabricating a living material with high cell viability and precise cell spatial distribution control. This cell-laden hydrogel platform accelerates the diabetic wound healing of rats based on the unabated vascular endothelial growth factor 165 release, which promotes angiogenesis and alleviates damages on vascular endothelial mitochondria, thereby reducing tissue hypoxia, downregulating inflammation, and facilitating extracellular matrix remodeling. Together, this study offers a promising strategy for fabricating tissue-friendly, high-efficient, and accurate 3D printed all-peptide hydrogel platform for cell delivery and self-renewable growth factor therapy.

Microfluidic intestinal organoid-on-a-chip uncovers therapeutic targets by recapitulating oxygen dynamics of intestinal IR injury.

Increasing evidence demonstrates that mammals have different reactions to hypoxia with varied oxygen dynamic patterns. It takes ∼24 h for tri-gas incubator to achieve steady cell hypoxia, which fails to recapitulate ultrafast oxygen dynamics of intestinal ischemia/reperfusion (IR) injury. Inspired from the structure of native intestinal villi, we engineered an intestinal organoid chip embedded with engineered artificial microvessels based on co-axial microfluidic technology by using pH-responsive ZIF-8/sodium alginate scaffold. The chip was featured on: (i) eight times the oxygen exchange efficiency compared with the conventional device, tri-gas incubator, (ii) implantation of intestinal organoid reproducing all types of intestinal epithelial cells, and (iii) bio-responsiveness to hypoxia and reoxygenation (HR) by presenting metabolism disorder, inflammatory reaction, and cell apoptosis. Strikingly, it was found for the first time that Olfactomedin 4 (Olfm4) was the most significantly down-regulated gene under a rapid HR condition by sequencing the RNA from the organoids. Mechanistically, OLFM4 played protective functions on HR-induced cell inflammation and tissue damage by inhibiting the NF-kappa B signaling activation, thus it could be used as a therapeutic target. Altogether, this study overcomes the issue of mismatched oxygen dynamics between in vitro and in vivo, and sets an example of next-generation multisystem-interactive organoid chip for finding precise therapeutic targets of IR injury.

Smart implants: 4D-printed shape-morphing scaffolds for medical implantation.

Biomedical implants have recently shown excellent application potential in tissue repair and replacement. Applying three-dimensional (3D) printing to implant scaffold fabrication can help to address individual needs more precisely. Fourdimensional (4D) printing emerges rapidly based on the development of shape-responsive materials and design methods, which makes the production of dynamic functional implants possible. Smart implants can be pre-designed to respond to endogenous or exogenous stimuli and perform seamless integration with regular/ irregular tissue defects, defect-luminal organs, or curved structures via programmed shape morphing. At the same time, they offer great advantages in minimally invasive surgery due to the small-to-large volume transition. In addition, 4D-printed cellular scaffolds can generate extracellular matrix (ECM)-mimetic structures that interact with the contacting cells, expanding the possible sources of tissue/organ grafts and substitutes. This review summarizes the typical technologies and materials of 4D-printed scaffolds, and the programming designs and applications of these scaffolds are further highlighted. Finally, we propose the prospects and outlook of 4D-printed shape-morphing implants.

Melt electrowriting-printed peritoneal scaffold prevents peritoneal adhesion and facilitates peritoneal repair.

Peritoneal adhesion is a critical issue after abdominal surgery. Cell-based methods for preventing peritoneal adhesion have not yet been fully investigated. Here, we constructed a highly biomimetic peritoneal scaffold by seeding mesothelial cells, the natural physiological barrier of the peritoneum, onto a melt electrowriting-printed scaffold. The scaffolds with the microfibers crossed at different angles (30°, 60°, and 90°) were screened based on mesothelial cell proliferation and orientation. Thirty degrees were more suitable for improving proliferation of mesothelial cells and cell growth in a single direction; therefore, the 30° peritoneal scaffold could better mimic the physiological structure of native peritoneum. Mechanistically, such a peritoneal scaffold was able to act as a barrier to prevent peritoneal resident macrophages from migrating to the site of the peritoneal lesion. In vivo mesothelial cell tracking using lentivirus technology confirmed that the peritoneal scaffold, compared to the scaffold without mesothelial cells, could prevent peritoneal adhesion and was directly involved in the repair of injured peritoneum. This study suggests that the peritoneal scaffolds can potentially prevent peritoneal adhesion, offering a new approach for clinical treatment.

Whole Model Path Planning-Guided Multi-Axis and Multi-Material Printing of High-Performance Intestinal Implantable Stent.

The problems of step effects, supporting material waste, and conflict between flexibility and toughness for 3D printed intestinal fistula stents are not yet resolved. Herein, the fabrication of a support-free segmental stent with two types of thermoplastic polyurethane (TPU) using a homemade multi-axis and multi-material conformal printer guided with advanced whole model path planning is demonstrated. One type of TPU segment is soft to increase elasticity, and the other is used to achieve toughness. Owing to advancements in stent design and printing, the obtained stents present three unprecedented properties compared to previous three-axis printed stents: i) Overcoming step effects; ii) Presenting comparable axial flexibility to a stent made of a single soft TPU 87A material, thus increasing the feasibility of implantation; and iii) Showing equivalent radial toughness to a stent made of a single hard TPU 95A material. Hence, the stent can resist the intestinal contractive force and maintain intestinal continuity and patency. Through implanting such stents to the rabbit intestinal fistula models, therapeutic mechanisms of reducing fistula output and improving nutritional states and intestinal flora abundance are revealed. Overall, this study develops a creative and versatile method to improve the poor quality and mechanical properties of medical stents.

Biomimetic Design of Double-Sided Functionalized Silver Nanoparticle/Bacterial Cellulose/Hydroxyapatite Hydrogel Mesh for Temporary Cranioplasty.

A structurally stable and antibacterial biomaterial used for temporary cranioplasty with guided bone regeneration (GBR) effects is an urgent clinical requirement. Herein, we reported the design of a biomimetic Ag/bacterial cellulose/hydroxyapatite (Ag/BC@HAp) hydrogel mesh with a double-sided functionalized structure, in which one layer was dense and covered with Ag nanoparticles and the other layer was porous and anchored with hydroxyapatite (HAp) via mineralization for different durations. Such a double-sided functionalized design endowed the hydrogel with distinguished antibacterial activities for inhibiting potential infections and GBR effects that could prevent endothelial cells and fibroblasts from migrating to a defected area and meanwhile show biocompatibility to MC3T3-E1 preosteoblasts. Furthermore, it was found from in vivo experimental results that the Ag/BC@HAp hydrogel with 7-day mineralization achieved optimal GBR effects by improving barrier functions toward these undesired cells. Moreover, this BC-based hydrogel mesh showed an extremely low swelling ratio and strong mechanical strength, which facilitated the protection of soft brain tissues without gaining the risk of intracranial pressure increase. In a word, this study offers a new approach to double-sided functionalized hydrogels and provides effective and safe biomaterials used for temporary cranioplasty with antibacterial abilities and GBR effects.

Extracellular matrix bioink boosts stemness and facilitates transplantation of intestinal organoids as a biosafe Matrigel alternative.

Organoids hold inestimable therapeutic potential in regenerative medicine and are increasingly serving as an in vitro research platform. Still, their expanding applications are critically restricted by the canonical culture matrix and system. Synthesis of a suitable bioink of bioactivity, biosecurity, tunable stiffness, and printability to replace conventional matrices and fabricate customized culture systems remains challenging. Here, we envisaged a novel bioink formulation based on decellularized extracellular matrix (dECM) from porcine small intestinal submucosa for organoids bioprinting, which provides intestinal stem cells (ISCs) with niche-specific ECM content and biomimetic microstructure. Intestinal organoids cultured in the fabricated bioink exhibited robust generation as well as a distinct differentiation pattern and transcriptomic signature. This bioink established a new co-culture system able to study interaction between epithelial homeostasis and submucosal cells and promote organoids maturation after transplantation into the mesentery of immune-deficient NODSCID-gamma (NSG) mice. In summary, the development of such photo-responsive bioink has the potential to replace tumor-derived Matrigel and facilitate the application of organoids in translational medicine and disease modeling.

Novel Temperature-Sensitive Hydrogel Promotes Wound Healing Through YAP and MEK-Mediated Mechanosensitivity.

Wound healing is a significant problem in clinical management. Various functional dressings are studied to promote wound healing through biochemical factors. They are generally expensive, complex to fabricate, and may adversely affect the wound. Mechanical forces are the critical regulators of tissue repair. Although contraction is shown to promote wound healing, the underlying mechanisms are not fully understood. In this study, a novel adhesive temperature-sensitive mechanically active hydrogel with a simple and inexpensive preparation process is developed. The dressing is able to adhere to the wound surface and actively contract the wound in response to body temperature. This mechanical contraction enhances the proliferative activity of basal cells, reduces the inflammatory response of the wound, and promotes wound healing. Furthermore, RNA-seq clarifies how the gene regulatory network is regulated by contraction. Finally, using pharmacological inhibitors, YAP and MEK are identified as the key signaling molecules for contraction-mediated tissue healing in vivo.

4D-printed bilayer hydrogel with adjustable bending degree for enteroatmospheric fistula closure.

Recently, four-dimensional (4D) shape-morphing structures, which can dynamically change shape over time, have attracted much attention in biomedical manufacturing. The 4D printing has the capacity to fabricate dynamic construction conforming to the natural bending of biological tissues, superior to other manufacturing techniques. In this study, we presented a multi-responsive, flexible, and biocompatible 4D-printed bilayer hydrogel based on acrylamide-acrylic acid/cellulose nanocrystal (AAm-AAc/CNC) network. The first layer was first stretched and then formed reversible coordination with Fe3+ to maintain this pre-stretched length; it was later combined with a second layer. The deformation process was actuated by the reduction of Fe3+ to Fe2+ in the first layer which restored it to its initial length. The deformation condition was to immerse the 4D construct in sodium lactate (LA-Na) and then expose it to ultraviolet (UV) light until maximal deformation was realized. The bending degree of this 4D construct can be programmed by modifying the pre-stretched lengths of the first layer. We explored various deformation steps in simple and complex constructs to verify that the 4D bilayer hydrogel can mimic the curved morphology of the intestines. The bilayer hydrogel can also curve in deionized water due to anisotropic volume change yet the response time and maximum bending degree was inferior to deformation in LA-Na and UV light. Finally, we made a 4D-printed bilayer hydrogel stent to test its closure effect for enteroatmospheric fistulas (EAFs) in vitro and in vivo. The results illustrate that the hydrogel plays a role in the temporary closure of EAFs. This study offers an effective method to produce curved structures and expands the potential applications of 4D printing in biomedical fields.

Multifunctional Electrospun Textiles for Wound Healing.

The novel multifunctional electrospun textiles were fabricated by incorporating sheet-like kaolinite and silver nanoparticles (AgNps) into a polyurethane (PU) textile by using electrostatic spinning to promote wound-healing process. Threedimensional network of PU electrospun textiles offered an appropriate framework for loading kaolinite nanosheets and AgNps. Moreover, the kaolinite nanosheets healed bleeding wounds by accelerating plasma absorption, increasing blood cell concentrations, and stimulating coagulation factors. Furthermore, the AgNps killed microbes by destroying the cell membrane, while the deleterious effects were controlled by incorporation into the electrospun textile. The therapeutic effects of multifunctional electrospun textile in treating full-thickness abdominal wall defect were explored. The wound healing process could be accelerated via the textile by restoring the abdominal physiological environment, reducing the inflammatory response, and promoting collagen deposition, angiogenesis, and epithelization.

Correction: Engineering an adhesive based on photosensitive polymer hydrogels and silver nanoparticles for wound healing.

Correction for 'Engineering an adhesive based on photosensitive polymer hydrogels and silver nanoparticles for wound healing' by Qinqing Tang et al., J. Mater. Chem. B, 2020, 8, 5756-5764, DOI: 10.1039/d0tb00726a.

Current knowledge on the multiform reconstitution of intestinal stem cell niche.

The development of "mini-guts" organoid originates from the identification of Lgr5+ intestinal stem cells (ISCs) and circumambient signalings within their specific niche at the crypt bottom. These in vitro self-renewing "mini-guts", also named enteroids or colonoids, undergo perpetual proliferation and regulated differentiation, which results in a high-performance, self-assembling and physiological organoid platform in diverse areas of intestinal research and therapy. The triumphant reconstitution of ISC niche in vitro also relies on Matrigel, a heterogeneous sarcoma extract. Despite the promising prospect of organoids research, their expanding applications are hampered by the canonical culture pattern, which reveals limitations such as inaccessible lumen, confine scale, batch to batch variation and low reproducibility. The tumor-origin of Matrigel also raises biosafety concerns in clinical treatment. However, the convergence of breakthroughs in cellular biology and bioengineering contribute to multiform reconstitution of the ISC niche. Herein, we review the recent advances in the microfabrication of intestinal organoids on hydrogel systems.

Mechanoadaptive injectable hydrogel based on poly(γ-glutamic acid) and hyaluronic acid regulates fibroblast migration for wound healing.

Injectable hydrogels have shown therapeutic effects on wound repair, but most of them exhibit poor mechanical strength. The impacts of stiff injectable hydrogels on cell behavior and wound healing remain unclear. Herein, an injectable hydrogel was developed based on thiolated poly(γ-glutamic acid) (γ-PGA-SH) and glycidyl methacrylate-conjuated oxidized hyaluronic acid (OHA-GMA). Thiol-methacrylate Michael chemistry-mediated post-stabilization and increase of polymer concentration were found to improve the mechanical strength of γ-PGA-SH/OHA-GMA hydrogel. Moreover, in vitro studies confirmed its biodegradability, biocompatibility, and self-healing property. Using the mechanically-tunable hydrogel, it further showed that fibroblasts migrated faster on the surface of stiffer hydrogel, but infiltrated slowly inside it compared with softer hydrogel. In animal experiments, the injectable hydrogel could promote wound healing by increasing collagen deposition and vascularization. In summary, γ-PGA-SH/OHA-GMA hydrogel is able to regulate migration and infiltration of fibroblasts by altering stiffness and offers effective in situ forming scaffolds towards skin tissue regeneration.

Fabrication of gelatin-based printable inks with improved stiffness as well as antibacterial and UV-shielding properties.

Gelatin-based inks have a broad range of applications in bioprinting for tissue engineering and regenerative medicine due to their biocompatibility, ease of modification, degradability, and rapid gelation induced by low temperature. However, gelatin-derived inks prepared through low-temperature treatment have poor mechanical properties that limit their applications. To solve this problem, we designed polyacrylamide/gelatin/silver nanoparticle (PAAm-GelatinAgNPs) ink to improve gelatin-based hydrogels. The ink is based on double networks, in which the physically cross-linked gelatin as the first network and covalently cross-linked PAAm as the second network. It was found that the presence of PAAm increased the tensile and compression strength of the gelatin-based ink. Moreover, silver nanoparticles endowed the antibacterial properties to the gelatin-based ink and were able to shield the UV irradiation and damages to rat skin. In addition, this ink showed the shear thinning property; Consequently it succeeded in printing complex 3D scaffolds such as the cube, five-pointed star, flower, and university logo of "SEU". In summary, this ink presents a new strategy for the modification of gelatin and offers new potential applications for customized therapy of antimicrobial and anti-UV damage to tissues.

Small Intestinalization of Colon Using Ileum Organoids.

Given the mismatch in size and morphology of intestinal organoids with native intestine, their application in intestinal segment regeneration has yet to be achieved. By engrafting ileal organoids in epithelium-removed colon, Sugimoto et al. recently constructed transplantable colonic segments with functional ileal epithelium and a subepithelial lymphovascular system, providing hope for the treatment of short bowel syndrome.