An injectable hydrogel microsphere-integrated training court to inspire tumor-infiltrating T lymphocyte potential.

Although tumor-infiltrating T lymphocytes (TIL-Ts) play a crucial role in solid tumor immunotherapy, their clinical application has been limited because of the immunosuppressive microenvironment. Herein, we developed an injectable hydrogel microsphere-integrated training court (MS-ITC) to inspire the function of TIL-Ts and amplify TIL-Ts, through grafting with anti-CD3 and anti-CD28 antibodies and bovine serum albumin nanoparticles encapsulated with IL-7 and IL-15. MS-ITC provided the T-cell receptor and co-stimulatory signals required for TIL-Ts activation and IL-7/IL-15 signals for TIL-Ts expansion. Afterward, the MS-ITC was injected locally into the osteosarcoma tumor tissue in mice. MS-ITC suppressed the growth of primary osteosarcoma by more than 95 %, accompanied with primed and expanded TIL-Ts in the tumor tissues, compromising significantly increased CD8+ T and memory T cells, thereby enhancing the anti-tumor effect. Together, this work provides an injectable hydrogel microsphere-integrated training platform capable of inspiring TIL-Ts potential for a range of solid tumor immunotherapy.

Bone Organoids: Recent Advances and Future Challenges.

Bone defects stemming from tumorous growths, traumatic events, and diverse conditions present a profound conundrum in clinical practice and research. While bone has the inherent ability to regenerate, substantial bone anomalies require bone regeneration techniques. Bone organoids represent a new concept in this field, involving the 3D self-assembly of bone-associated stem cells guided in vitro with or without extracellular matrix material, resulting in a tissue that mimics the structural, functional, and genetic properties of native bone tissue. Within the scientific panorama, bone organoids ascend to an esteemed status, securing significant experimental endorsement. Through a synthesis of current literature and pioneering studies, this review offers a comprehensive survey of the bone organoid paradigm, delves into the quintessential architecture and ontogeny of bone, and highlights the latest progress in bone organoid fabrication. Further, existing challenges and prospective directions for future research are identified, advocating for interdisciplinary collaboration to fully harness the potential of this burgeoning domain. Conclusively, as bone organoid technology continues to mature, its implications for both clinical and research landscapes are poised to be profound.

Intestine-Targeted Explosive Hydrogel Microsphere Promotes Uric Acid Excretion for Gout Therapy.

Uric acid metabolism disorder triggers metabolic diseases, especially gout. However, increasing uric acid excretion remains a challenge. Here, an accelerative uric acid excretion pathway via an oral intestine-explosive hydrogel microsphere merely containing uricase and dopamine is reported. After oral administration, uricase is exposed and immobilized on intestinal mucosa along with an in situ dopamine polymerization via a cascade reaction triggered by the intestinal specific environment. By this means, trace amount of uricase is required to in situ up-regulate uric acid transporter proteins of intestinal epithelial cells, causing accelerated intestinal uric acid excretion. From in vitro data, the uric acid in fecal samples from gout patients could be significantly reduced by up to 37% by the mimic mucosa-immobilized uricase on the isolated porcine tissues. Both hyperuricemia and acute gouty arthritis in vivo mouse models confirm the uric acid excretion efficacy of intestine-explosive hydrogel microspheres. Fecal uric acid excretion is increased around 30% and blood uric acid is reduced more than 70%. In addition, 16S ribosomal RNA sequencing showed that the microspheres optimized intestinal flora composition as well. In conclusion, a unique pathway via the intestine in situ regulation to realize an efficient uric acid intestinal excretion for gout therapy is developed.

Seamlessly Adhesive Bionic Periosteum Patches Via Filling Microcracks for Defective Bone Healing.

Current artificial designs of the periosteum focus on osteogenic or angiogenic properties, while ignoring the filling and integration with bone microcracks, which trigger a prolonged excessive inflammatory reaction and lead to failure of bone regeneration. In this study, seamless adhesive biomimetic periosteum patches (HABP/Sr-PLA) were prepared to fill microcracks in defective bone via interfacial self-assembly induced by Sr ions mediated metal-ligand interactions among pamidronate disodium-modified hyaluronic acid (HAPD), black phosphorus (BP), and hydrophilic polylactic acid (PLA). In vitro, HABP/Sr-PLA exhibited excellent self-healing properties, seamlessly filled bone microcracks, and significantly enhanced osteogenesis and angiogenesis. Furthermore, in a rat cranial defect model, HABP/Sr-PLA was demonstrated to significantly promote the formation of blood vessels and new bone under mild 808 nm photothermal stimulation (42.8 °C), and the highest protein expression of CD31 and OPN was five times higher than that of the control group and other groups. Therefore, the proposed seamless microcrack-filled bionic periosteum patch is a promising clinical strategy for promoting bone repair.

Engineered Living Oriented Electrospun Fibers Regulate Stem Cell Para-Secretion and Differentiation to Promote Spinal Cord Repair.

Living biomaterials directly couple with live cells to synthesize functional molecules and respond to dynamic environments, allowing the design, construction and application of next generation composite materials. Improving the coordination and communication between artificial materials and living cells is essential. In this study, collagen self-assembly and micro-sol electrospinning techniques are used to prepare oriented living fiber bundles that can increase the transplantation rate of stem cells in the early stages of inflammation, indirectly enhancing the dynamic regulation of stem cells during inflammation. Additionally, brain-derived neurotrophic factor (BDNF) contained in the fiber can improve the differentiation of bone marrow mesenchymal stem cells (BMSCs) into neurons once the inflammatory storm subsides. The living oriented fiber bundles fully simulate the 3D structure of the central nervous system, activate integrin ß1, promote the growth and adhesion of stem cells in the acute stage of inflammation, upregulate anti-inflammatory genes by more than twofold via BMSCs in response to inflammation, and stably release BDNF for up to 4 weeks post-inflammation storm subsidence. Finally, the BDNF induces the differentiation of BMSCs to neurons by enhancing the expression of neural-related genes, which enables the recovery of neurological functions in the later stages of spinal cord injury.

3D bioprinting of emulating homeostasis regulation for regenerative medicine applications.

Homeostasis is the most fundamental mechanism of physiological processes, occurring simultaneously as the production and outcomes of pathological procedures. Accompanied by manufacture and maturation of intricate and highly hierarchical architecture obtained from 3D bioprinting (three-dimension bioprinting), homeostasis has substantially determined the quality of printed tissues and organs. Instead of only shape imitation that has been the remarkable advances, fabrication for functionality to make artificial tissues and organs that act as real ones in vivo has been accepted as the optimized strategy in 3D bioprinting for the next several years. Herein, this review aims to provide not only an overview of 3D bioprinting, but also the main strategies used for homeostasis bioprinting. This paper briefly introduces the principles of 3D bioprinting system applied in homeostasis regulations firstly, and then summarizes the specific strategies and potential trend of homeostasis regulations using multiple types of stimuli-response biomaterials to maintain auto regulation, specifically displaying a brilliant prospect in hormone regulation of homeostasis with the most recently outbreak of vasculature fabrication. Finally, we discuss challenges and future prospects of homeostasis fabrication based on 3D bioprinting in regenerative medicine, hoping to further inspire the development of functional fabrication in 3D bioprinting.

Functional biomaterials for tendon/ligament repair and regeneration.

With an increase in life expectancy and the popularity of high-intensity exercise, the frequency of tendon and ligament injuries has also increased. Owing to the specificity of its tissue, the rapid restoration of injured tendons and ligaments is challenging for treatment. This review summarizes the latest progress in cells, biomaterials, active molecules and construction technology in treating tendon/ligament injuries. The characteristics of supports made of different materials and the development and application of different manufacturing methods are discussed. The development of natural polymers, synthetic polymers and composite materials has boosted the use of scaffolds. In addition, the development of electrospinning and hydrogel technology has diversified the production and treatment of materials. First, this article briefly introduces the structure, function and biological characteristics of tendons/ligaments. Then, it summarizes the advantages and disadvantages of different materials, such as natural polymer scaffolds, synthetic polymer scaffolds, composite scaffolds and extracellular matrix (ECM)-derived biological scaffolds, in the application of tendon/ligament regeneration. We then discuss the latest applications of electrospun fiber scaffolds and hydrogels in regeneration engineering. Finally, we discuss the current problems and future directions in the development of biomaterials for restoring damaged tendons and ligaments.

Immunology and bioinformatics analysis of injectable organic/inorganic microfluidic microspheres for promoting bone repair.

Organic/inorganic composites have advantages in promoting bone repair; however, early changes in the local immune response after material implantation and the mechanisms that affect the late osteogenesis have not been revealed systematically. Herein, we prepared injectable composite poly (l-lactic acid)/nano hydroxyapatite (PLLA/nHA) porous microspheres (MS@SL@nHA) using a microfluidic technology to explore the changes in the osteo-immune microenvironment and potential mechanisms using immunology and bioinformatics. Immunological analysis revealed that macrophages (Mφ) phagocytosed the nHA released from the composite microspheres, increased the proportion of M2 Mφ, regulated the early inflammatory response, exerted strong paracrine effects, and improved the osteo-immune microenvironment. Bioinformatics analysis showed that the signal transduction and adhesion ability were enhanced after Mφ activation, the inflammatory signaling pathways were inhibited, regulating the polarization direction, and the expression of cell growth factors was up-regulated to promote late osteogenesis. In vivo studies demonstrated that the composite microspheres effectively regulated Mφ polarization, and the paracrine secreted growth factors created a microsphere-centered osteogenesis pattern at the defect site. In conclusion, we successfully prepared injectable composite PLLA/nHA porous microspheres and systematically explored the osteogenesis-related mechanisms using immunological and bioinformatics analysis to provide theoretical evidence for bone repair materials that contribute to bone differentiation.

Nanofat functionalized injectable super-lubricating microfluidic microspheres for treatment of osteoarthritis.

Nanofat (NF) is a fine emulsion that has been used to treat a variety of diseases given its abundance of bioactive components. However, the biological functions of NF have been limited due to its inability to localize during implantation. In this study, NF was immobilized in microfluidic-generated aldehyde-modified polylactic glycolic acid (PLGA) porous microspheres (PMs) via Schiff base condensation and non-covalent binding in a three-dimensional (3D) porous network (PMs@NF). The PMs effectively enhanced the cartilage-targeted retention efficiency of NF, which also resulted in remarkable lubrication performance, with the friction coefficient being reduced by ∼80%, which was maintained over time. Meanwhile, the 3D penetrating structure of the microspheres stimulated cytokine secretion by the NF-derived stem cells, upregulating the expression of anabolism-related genes and downregulating catabolism, and the expression of inflammation-related and pain-related genes. Injecting PMs@NF into the knee joint cavity of a rat model with destabilization of the medial meniscus (DMM) reduced osteophyte formation and protected the cartilage from degeneration, thereby inhibiting the progression of osteoarthritis and improving animal behavior. In summary, this study developed a multifunctional platform with NF immobilization and super-lubrication, which showed great potential for the minimally invasive treatment of osteoarthritis.

A Biomaterial-Based Hedging Immune Strategy for Scarless Tendon Healing.

Scarring rather than regeneration, is an inevitable outcome of unbalanced amplifications of inflammation-destructive signals and atresia of the regenerative niche. However, identifying and effectively hedging against the risk of scarring and realizing the conversion of regenerative cues remain difficult. In this work, a hedging immune strategy based microfibrous membrane (Him-MFM), by tethering distearoyl phosphoethanolamine layer-supported copoly(lactic/glycolic acid) electrospun fibers with identified CD11b+ /CD68+ scarring subpopulation membranes in the immune landscape after tendon injury to counterweigh tissue damage, is reported. Him-MFM, carrying relevant risk receptors is shown to shift high type I biased polarization, alleviate apoptosis and metabolic stress, and mitigate inflammatory tenocyte response. Remarkably, the hedging immune strategy reverses the damaged tendon sheath barrier to the innate IL-33 secretory phenotype by 4.36 times and initiates the mucous-IL-33-Th2 axis, directly supplying a transient but obligate regenerative niche for sheath stem cell proliferation. In murine flexor tendon injury, the wrapping of Him-MFM alleviates pathological responses, protects tenocytes in situ, and restores hierarchically arranged collagen fibers covered with basement membrane, and is structurally and functionally comparable to mature tendons, demonstrating that the hedging immunity is a promising strategy to yield regenerative responses not scarring.