3D Printed Calcium Phosphate Physiochemically Dual-Regulating Pro-Osteogenesis and Antiosteolysis for Enhancing Bone Tissue Regeneration.

Osteoblasts and osteoclasts are two of the most important types of cells in bone repair, and their bone-forming and bone-resorbing activities influence the process of bone repair. In this study, we proposed a physicochemical bidirectional regulation strategy via ration by physically utilizing hydroxyapatite nanopatterning to recruit and induce MSCs osteogenic differentiation and by chemically inhibiting osteolysis activity through the loaded zoledronate. The nanorod-like hydroxyapatite coating was fabricated via a modified hydrothermal process while the zoledronic acid was loaded through the chelation within the calcium ions. The fabrication of a hydroxyapatite/zoledronic acid composite biomaterial. This biomaterial promotes bone tissue regeneration by physically utilizing hydroxyapatite nanopatterning to recruit and induce MSCs osteogenic differentiation and by chemically inhibiting osteolysis activity through the loaded zoledronate. The nanorod-like hydroxyapatite coating was fabricated via a modified hydrothermal process while the zoledronic acid was loaded through the chelation within the calcium ions. The in vitro results tested on MSCs and RAW 246.7 indicated that the hydroxyapatite enhanced cells' physical sensing system, therefore enhancing the osteogenesis. At the same time the zoledronic acid inhibited osteolysis by downregulating the RANK-related genes. This research provides a promising strategy for enhancing bone regeneration and contributes to the field of orthopedic implants.

Cisplatin-based miRNA delivery strategy inspired by the circCPNE1/miR-330-3p pathway for oral squamous cell carcinoma.

Circular RNAs (circRNAs) are ideal biomarkers of oral squamous cell carcinoma (OSCC) because of their highly stable closed-loop structure, and they can act as microRNA (miRNA) sponges to regulate OSCC progression. By analyzing clinical samples, we identified circCPNE1, a dysregulated circRNA in OSCC, and its expression level was negatively correlated with the clinical stage of OSCC patients. Gain-of-function assays revealed the tumor-suppressive effect of circCPNE1, which was then identified as a miR-330-3p sponge. MiR-330-3p was recognized as a tumor promoter in multiple studies, consistent with our finding that it could promote the proliferation, migration, and invasion of OSCC cells. These results indicated that selective inhibition of miR-330-3p could be an effective strategy to inhibit OSCC progression. Therefore, we designed cationic polylysine-cisplatin prodrugs to deliver antagomiR-330-3p (a miRNA inhibitory analog) via electrostatic interactions to form PP@miR nanoparticles (NPs). Paratumoral administration results revealed that PP@miR NPs effectively inhibited subcutaneous tumor progression and achieved partial tumor elimination (2/5), which confirmed the critical role of miR-330-3p in OSCC development. These findings provide a new perspective for the development of OSCC treatments.

Hyaluronated nanohydroxyapatite responsively released from injectable hydrogels for targeted therapy of melanoma.

Nanohydroxyapatite (nHAp) has attracted significant attention for its tumor suppression and tumor microenvironment modulation capabilities. However, a strong tendency to aggregate greatly affects its anti-tumor efficiency. To address this issue, a hydrogel platform consisting of thiolated hyaluronic acid (HA-SH) modified nanohydroxyapatite (nHAp-HA) and HA-SH was developed for sustained delivery of nHAp for melanoma therapy. The hydrophilic and negatively charged HA-SH significantly improved the size dispersion and stability of nHAp in aqueous media while conferring nHAp targeting effects. Covalent sulfhydryl self-cross-linking between HA-SH and nHAp-HA groups ensured homogeneous dispersion of nHAp in the matrix material. Meanwhile, the modification of HA-SH conferred the targeting properties of nHAp and enhanced cellular uptake through the HA/CD44 receptor. The hydrogel platform could effectively reduce the aggregation of nHAp and release nHAp in a sustained and orderly manner. Antitumor experiments showed that the modified nHAp-HA retained the tumor cytotoxicity of nHAp in vitro and inhibited the growth of highly malignant melanomas up to 78.6% while being able to induce the differentiation of macrophages to the M1 pro-inflammatory and antitumor phenotype. This study will broaden the application of nanohydroxyapatite in tumor therapy.

Microenvironment-responsive release of Mg2+ from tannic acid decorated and multilevel crosslinked hydrogels accelerates infected wound healing.

The management of chronic infected wounds poses significant challenges due to frequent bacterial infections, high concentrations of reactive oxygen species, abnormal immune regulation, and impaired angiogenesis. This study introduces a novel, microenvironment-responsive, dual dynamic, and covalently bonded hydrogel, termed OHA-P-TA/G/Mg2+. It is derived from the reaction of tannic acid (TA) with phenylboronic acids (PBA), which are grafted onto oxidized hyaluronic acid (OHA-P-TA), combined with GelMA (G) via a Schiff base and chemical bonds, along with the incorporation of Mg2+. This hydrogel exhibits pH and ROS dual-responsiveness, demonstrating effective antibacterial capacity, antioxidant ability, and the anti-inflammatory ability under distinct acidic and oxidative microenvironments. Furthermore, the release of Mg2+ from the TA-Mg2+ network (TA@Mg2+) promotes the transformation of pro-inflammatory M1 phenotype macrophages to anti-inflammatory M2 phenotype, showing a microenvironment-responsive response. Finally, in vivo results indicate that the OHA-P-TA/G/Mg2+ hydrogel enhances epithelial regeneration, collagen deposition, and neovascularization, showing great potential as an effective dressing for infected wound repair.

A Redox-Triggered Autophagy-Induced Nanoplatform with PD-L1 Inhibition for Enhancing Combined Chemo-Immunotherapy.

Epirubicin (EPI) alone can trigger mildly protective autophagy in residual tumor cells, resulting in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and leads to antiprogrammed death ligand 1 (anti-PD-1)/PD-L1 therapy resistance, posing a significant clinical challenge in tumor immunotherapy. The combination of checkpoint inhibitors targeting the PD-1/PD-L1 pathway and amplifying autophagy presents an innovative approach to tumor treatment, which can prevent tumor immune escape and enhance therapeutic recognition. Herein, we aimed to synthesize a redox-triggered autophagy-induced nanoplatform with SA&EA-induced PD-L1 inhibition. The hyaluronic acid (HA) skeleton and arginine segment promoted active nanoplatform targeting, cell uptake, and penetration. The PLGLAG peptide was cleaved by overexpressing matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, and the PD-L1 inhibitor D-PPA was released to inhibit tumor immune escape. The intense autophagy inducers, STF-62247 and EPI, were released owing to the cleavage of disulfide bonds influenced by the high glutathione (GSH) concentration in tumor cells. The combination of EPI and STF induced apoptosis and autophagic cell death, effectively eliminating a majority of tumor cells. This indicated that the SA&EA nanoplatform has better therapeutic efficacy than the single STF@AHMPP and EPI@AHMPTP groups. This research provided a way to set up a redox-triggered autophagy-induced nanoplatform with PD-L1 inhibition to enhance chemo-immunotherapy.

3D printing of customized bioceramics for promoting bone tissue regeneration by regulating sympathetic nerve behavior.

Numerous studies have shown that there are multiple neural activities involved in the process of bone resorption and bone regeneration, and promoting osteogenesis by promoting neural network reconstruction is an effective strategy for repairing critical size bone defects. However, traumatic bone defects often cause activation of the sympathetic nervous system (SNS) in the damaged area, releasing excess catecholamines (CAs), resulting in a decrease in the rate of bone formation. Herein, a 3D-printed scaffold loaded with propranolol (PRN) is proposed to reduce CA concentrations in bone defect areas and promote bone regeneration through drug release. For this purpose, PRN-loaded methacrylated gelatin (GelMA) microspheres were mixed with low-concentration GelMA and perfused into a 3D-printed porous hydroxyapatite (HAp) scaffold. By releasing PRN, which can block ß-adrenergic receptors, it hinders the activation of sympathetic nerves and inhibits the release of excess CA by the SNS. At the same time, the composite scaffold recruits bone marrow mesenchymal stem cells (BMSCs) and promotes the differentiation of BMSCs in the direction of osteoblasts, which effectively promotes bone regeneration in the rabbit femoral condyle defect model. The results of the study showed that the release of PRN from the composite scaffold could effectively hinder the activation of sympathetic nerves and promote bone regeneration, providing a new strategy for the treatment of bone defects.

Molecular co-assembled strategy tuning protein conformation for cartilage regeneration.

The assembly of oligopeptide and polypeptide molecules can reconstruct various ordered advanced structures through intermolecular interactions to achieve protein-like biofunction. Here, we develop a "molecular velcro"-inspired peptide and gelatin co-assembly strategy, in which amphiphilic supramolecular tripeptides are attached to the molecular chain of gelatin methacryloyl via intra-/intermolecular interactions. We perform molecular docking and dynamics simulations to demonstrate the feasibility of this strategy and reveal the advanced structural transition of the co-assembled hydrogel, which brings more ordered ß-sheet content and 10-fold or more compressive strength improvement. We conduct transcriptome analysis to reveal the role of co-assembled hydrogel in promoting cell proliferation and chondrogenic differentiation. Subcutaneous implantation evaluation confirms considerably reduced inflammatory responses and immunogenicity in comparison with type I collagen. We demonstrate that bone mesenchymal stem cells-laden co-assembled hydrogel can be stably fixed in rabbit knee joint defects by photocuring, which significantly facilitates hyaline cartilage regeneration after three months. This co-assembly strategy provides an approach for developing cartilage regenerative biomaterials.

Engineered Microchannel Scaffolds with Instructive Niches Reinforce Endogenous Bone Regeneration by Regulating CSF-1/CSF-1R Pathway.

Structural and physiological cues provide guidance for the directional migration and spatial organization of endogenous cells. Here, a microchannel scaffold with instructive niches is developed using a circumferential freeze-casting technique with an alkaline salting-out strategy. Thereinto, polydopamine-coated nano-hydroxyapatite is employed as a functional inorganic linker to participate in the entanglement and crystallization of chitosan molecules. This scaffold orchestrates the advantage of an oriented porous structure for rapid cell infiltration and satisfactory immunomodulatory capacity to promote stem cell recruitment, retention, and subsequent osteogenic differentiation. Transcriptomic analysis as well as its in vitro and in vivo verification demonstrates that essential colony-stimulating factor-1 (CSF-1) factor is induced by this scaffold, and effectively bound to the target colony-stimulating factor-1 receptor (CSF-1R) on the macrophage surface to activate the M2 phenotype, achieving substantial endogenous bone regeneration. This strategy provides a simple and efficient approach for engineering inducible bone regenerative biomaterials.

Hierarchical Scaffold with Directional Microchannels Promotes Cell Ingrowth for Bone Regeneration.

Bone regenerative scaffolds with a bionic natural bone hierarchical porous structure provide a suitable microenvironment for cell migration and proliferation. Here, a bionic scaffold (DP-PLGA/HAp) with directional microchannels is prepared by combining 3D printing and directional freezing technology. The 3D printed framework provides structural support for new bone tissue growth, while the directional pore embedded in the scaffolds provides an express lane for cell migration and nutrition transport, facilitating cell growth and differentiation. The hierarchical porous scaffolds achieve rapid infiltration and adhesion of bone marrow mesenchymal stem cells (BMSCs) and improve the expression of osteogenesis-related genes. The rabbit cranial defect experiment presents significant new bone formation, demonstrating that DP-PLGA/HAp offers an effective means to guide cranial bone regeneration. The combination of 3D printing and directional freezing technology might be a promising strategy for developing bone regenerative biomaterials.

A facile Immunoregulatory Constructional Design by Proanthocyanidin Optimizing Directional Chitosan Microchannel.

Improving the interconnected structure and bioregulatory function of natural chitosan is beneficial for optimizing its performance in bone regeneration. Here, a facile immunoregulatory constructional design is proposed for developing instructive chitosan by directional freezing and alkaline salting out. The molecular dynamics simulation confirmed the assembly kinetics and structural features of various polyphenols and chitosan molecules. Along with the in vitro anti-inflammatory, antioxidative, promoting bone mesenchymal stem cell (BMSC) adhesion and proliferation performance, proanthocyanidin optimizing chitosan (ChiO) scaffold presented an optimal immunoregulatory structure with the directional microchannel. Transcriptome analysis in vitro further revealed the cytoskeleton- and immune-regulation effect of ChiO are the key mechanism of action on BMSC. The rabbit cranial defect model (Φ = 10 mm) after 12 weeks of implantation confirmed the significantly enhanced bone reconstitution. This facile immunoregulatory directional microchannel design provides effective guidance for developing inducible chitosan scaffolds.

Injectable Microgels with Hybrid Exosomes of Chondrocyte-Targeted FGF18 Gene-Editing and Self-Renewable Lubrication for Osteoarthritis Therapy.

Abnormal silencing of fibroblast growth factor (FGF) signaling significantly contributes to joint dysplasia and osteoarthritis (OA); However, the clinical translation of FGF18-based protein drugs is hindered by their short half-life, low delivery efficiency and the need for repeated articular injections. This study proposes a CRISPR/Cas9-based approach to effectively activate the FGF18 gene of OA chondrocytes at the genome level in vivo, using chondrocyte-affinity peptide (CAP) incorporated hybrid exosomes (CAP/FGF18-hyEXO) loaded with an FGF18-targeted gene-editing tool. Furthermore, CAP/FGF18-hyEXO are encapsulated in methacrylic anhydride-modified hyaluronic (HAMA) hydrogel microspheres via microfluidics and photopolymerization to create an injectable microgel system (CAP/FGF18-hyEXO@HMs) with self-renewable hydration layers to provide persistent lubrication in response to frictional wear. Together, the injectable CAP/FGF18-hyEXO@HMs, combined with in vivo FGF18 gene editing and continuous lubrication, have demonstrated their capacity to synergistically promote cartilage regeneration, decrease inflammation, and prevent ECM degradation both in vitro and in vivo, holding great potential for clinical translation.

Cell-Free Osteoarthritis Treatment with Sustained-Release of Chondrocyte-Targeting Exosomes from Umbilical Cord-Derived Mesenchymal Stem Cells to Rejuvenate Aging Chondrocytes.

As chondrocytes from osteoarthritic cartilage usually exhibit aging and senescent characteristics, targeting aging chondrocytes could be a potential therapeutic strategy. In this study, exosomes derived from umbilical cord-derived mesenchymal stem cells (UCMSC-EXOs) combined with the chondrocyte-targeting capacity and controlled-release system were proposed for osteoarthritis (OA) treatment via rejuvenating aging chondrocytes. The essential functional miRNAs within UCMSC-EXOs were investigated, with the p53 signaling pathway identified as the key factor. To improve the therapeutic efficiency and retention time of UCMSC-EXOs in vivo, the exosomes (EXOs) were engineered on membranes with a designed chondrocyte-targeting polymers, and encapsulated within thiolated hyaluronic acid microgels to form a "two-phase" releasing system, which synergistically facilitated the repair of OA cartilage in a rat model. Together, this study highlighted the rejuvenating effects of UCMSC-EXOs on OA chondrocytes and the potential to combine with chondrocyte-targeting and sustained-release strategies toward a future cell-free OA treatment.

A chitosan-optimized polyethyleneimine/polyacrylic acid multifunctional hydrogel for reducing the risk of ulcerative arterial bleeding.

Ulcerative arterial bleeding is characterized by sudden onset, rapid disease development, and high mortality, which is a great challenge for clinicians to treat, specially bleeding in areas where endoscopic operation is difficult, or in the case of diffuse bleeding, tumor bleeding, and recurrent bleeding. Herein, we proposed a novel treatment strategy using biomaterials to protect the wound and isolate the erosion of digestive tract contents to prevent arterial bleeding in advance. By introducing chitosan to construct multihydrogen-bonding and an electrostatic interaction system, we developed polyethyleneimine/polyacrylic acid/chitosan (PEI/PAA/CS) multifunctional hydrogel. The new hydrogel is characterized by ultrafast gelation, strong tissue adhesion, gastric acid resistance, burst resistance, biocompatibility, hemostasis, and tissue repair. The addition of CS significantly improved the tissue adhesion, biocompatibility, hemostasis, and tissue repair ability of the hydrogel. The PEI/PAA/CS hydrogel could adhere to the ulcer surface and form a protective layer on the wound to prevent arterial bleeding. Importantly, the PEI/PAA/CS hydrogel also has the ability to stop bleeding and promote wound repair, which has been demonstrated in a variety of hemorrhage models in rats and rabbits. All of these factors indicate that the PEI/PAA/CS hydrogel is a promising biomaterial for reducing the risk of ulcerative arterial bleeding.

LncRNA SELL/L-selectin promotes HPV-positive HNSCC progression and drives fucoidan-mediated therapeutic strategies.

Positive human papillomavirus (HPV+) head and neck squamous cell carcinoma (HNSCC) presents a higher risk of lymph node metastasis and poor prognosis. Here, advanced microarray analysis of clinically collected HNSCC tissues revealed significant upregulation of the lncRNA SELL in HPV+ HNSCC, and its overexpression was obviously associated with lymph node metastasis. The lncRNA SELL could function as a promigratory and proinvasive mediator as well as an inducer of M1-like tumour-associated macrophages (TAM) by increasing the level of L-selectin. Furthermore, fucoidan, as an L-selectin inhibitor, obviously weakened the formation of tongue lesions induced by 4-Nitroquinoline N-oxide (4-NQO) in HPV16 E6/E7 transgenic mice. This result drove us to synchronously develop a nanodelivery platform to verify fucoidan-mediated anti-growth and anti-metastasis effects. This work highlighted the important influence of the lncRNA SELL/L-selectin on promoting HPV+ HNSCC progression and proposed a potential fucoidan-mediated therapeutic strategy. STATEMENT OF SIGNIFICANCE: Head and neck squamous cell carcinoma (HNSCC) patients with human papillomavirus (HPV) involvement present a greater risk of lymph node metastasis than HPV negative HNSCC patients. However, treatment protocols, including surgery and platinum-based chemo- and radiotherapy, have not improved the 5-year overall survival due to the high tendency of lymphatic metastasis. Here, microarray of clinical HNSCC samples confirms the oncogenic significance of lncRNA SELL, which acts as an M1-like TAM inducer and promotes tumorigenesis by upregulating L-selectin. Fucoidan, as an L-selectin inhibitor, suppresses tongue lesions in transgenic mice, and a fucoidan-mediated nanodelivery platform inhibits HPV+ HNSCC growth. The present study highlights lncRNA SELL/L-selectin on promoting HPV+ HNSCC progression and proposes a potential fucoidan-mediated therapeutic.

Functional injectable hydrogel with spatiotemporal sequential release for recruitment of endogenous stem cells and in situ cartilage regeneration.

Articular cartilage is refractory to self-healing due to the absence of vascular, nervous, and lymphatic systems, and its repair remains a clinical challenge. Tissue regeneration through in situ recruitment of stem cells via cell-free scaffolds is a promising alternative strategy. Herein, a kind of functional injectable hydrogel system (Col-Apt@KGN MPs), which is a collagen-based and microsphere-embedded cell-free scaffold, was designed to achieve spatiotemporal regulation of endogenous mesenchymal stem cells (MSCs) recruitment and their chondrogenic differentiation by respective release of aptamer 19S (Apt19S) and kartogenin (KGN). In vitro results confirmed that the Col-Apt@KGN MPs hydrogel had sequential release characteristics. Apt19S was rapidly released from the hydrogel within 6 days, while KGN was slowly released for 33 days via the degradation of poly(lactic-co-glycolic acid) (PLGA) microspheres. When cultured with MSCs, the Col-Apt@KGN MPs hydrogel supported the adhesion, proliferation, and chondrogenic differentiation of MSCs. In vivo results indicated that the Col-Apt@KGN MPs hydrogel effectively promoted the recruitment of endogenous MSCs in a rabbit full-thickness cartilage defect model; furthermore, the Col-Apt@KGN MPs hydrogel enhanced the secretion of cartilage specific extracellular matrix and achieved the reconstruction of subchondral bone. This study demonstrates that the Col-Apt@KGN MPs hydrogel possesses great potential in recruitment of endogenous stem cells and cartilage tissue regeneration.

Electrospun Hyaluronan Nanofiber Membrane Immobilizing Aromatic Doxorubicin as Therapeutic and Regenerative Biomaterial.

Lesioned tissue requires synchronous control of disease and regeneration progression after surgery. It is necessary to develop therapeutic and regenerative scaffolds. Here, hyaluronic acid (HA) was esterified with benzyl groups to prepare hyaluronic acid derivative (HA-Bn) nanofibers via electrospinning. Electrospun membranes with average fiber diameters of 407.64 ± 124.8 nm (H400), 642.3 ± 228.76 nm (H600), and 841.09 ± 236.86 nm (H800) were obtained by adjusting the spinning parameters. These fibrous membranes had good biocompatibility, among which the H400 group could promote the proliferation and spread of L929 cells. Using the postoperative treatment of malignant skin melanoma as an example, the anticancer drug doxorubicin (DOX) was encapsulated in nanofibers via hybrid electrospinning. The UV spectroscopy of DOX-loaded nanofibers (HA-DOX) revealed that DOX was successfully encapsulated, and there was a π-π interaction between aromatic DOX and HA-Bn. The drug release profile confirmed the sustained release of about 90%, achieved within 7 days. In vitro cell experiments proved that the HA-DOX nanofiber had a considerable inhibitory effect on B16F10 cells. Therefore, the HA-Bn electrospun membrane could facilitate the potential regeneration of injured skin tissues and be incorporated with drugs to achieve therapeutic effects, offering a powerful approach to developing therapeutic and regenerative biomaterial.

Nanostructured 3D-Printed Hybrid Scaffold Accelerates Bone Regeneration by Photointegrating Nanohydroxyapatite.

Nanostructured biomaterials that replicate natural bone architecture are expected to facilitate bone regeneration. Here, nanohydroxyapatite (nHAp) with vinyl surface modification is acquired by silicon-based coupling agent and photointegrated with methacrylic anhydride-modified gelatin to manufacture a chemically integrated 3D-printed hybrid bone scaffold (75.6 wt% solid content). This nanostructured procedure significantly increases its storage modulus by 19.43-fold (79.2 kPa) to construct a more stable mechanical structure. Furthermore, biofunctional hydrogel with biomimetic extracellular matrix is anchored onto the filament of 3D-printed hybrid scaffold (HGel-g-nHAp) by polyphenol-mediated multiple chemical reactions, which contributes to initiate early osteogenesis and angiogenesis by recruiting endogenous stem cells in situ. Significant ectopic mineral deposition is also observed in subcutaneously implanted nude mice with storage modulus enhancement of 25.3-fold after 30 days. Meanwhile, HGel-g-nHAp realizes substantial bone reconstruction in the rabbit cranial defect model, achieving 61.3% breaking load strength and 73.1% bone volume fractions in comparison to natural cranium 15 weeks after implantation. This optical integration strategy of vinyl modified nHAp provides a prospective structural design for regenerative 3D-printed bone scaffold.

Bioabsorbable nano-micelle hybridized hydrogel scaffold prevents postoperative melanoma recurrence.

The residual and scattered small tumor tissue or cells after surgery are the main reason for tumor recurrence. Chemotherapy has a powerful ability to eradicate tumors but always accompanied by serious side effects. In this work, tissue-affinity mercapto gelatin (GelS) and dopamine-modified hyaluronic acid (HAD) were employed to fabricate a hybridized cross-linked hydrogel scaffold (HG) by multiple chemical reactions, which could integrate the doxorubicin (DOX) loaded reduction-responsive nano-micelle (PP/DOX) into this scaffold via click reaction to obtain the bioabsorbable nano-micelle hybridized hydrogel scaffold (HGMP). With the degradation of HGMP, PP/DOX was slowly released and formed targeted PP/DOX with degraded gelatin fragments as target molecules, which increased the intracellular accumulation, and inhibited the aggregation of B16F10 cells in vitro. In mouse models, HGMP absorbed the scattered B16F10 cells and released targeted PP/DOX to suppress tumorigenesis. For another, implantation of HGMP at the surgical site reduced the recurrence rate of postoperative melanoma and inhibited the growth of recurrent tumors. Meanwhile, HGMP significantly relieved the damage of free DOX to hair follicle tissue. This bioabsorbable nano-micelle hybridized hydrogel scaffold provided a valuable strategy for adjuvant therapy after tumor surgery.

Covalently Grafted Biomimetic Matrix Reconstructs the Regenerative Microenvironment of the Porous Gradient Polycaprolactone Scaffold to Accelerate Bone Remodeling.

Integrating a biomimetic extracellular matrix to improve the microenvironment of 3D printing scaffolds is an emerging strategy for bone substitute design. Here, a "soft-hard" bone implant (BM-g-DPCL) consisting of a bioactive matrix chemically integrated on a polydopamine (PDA)-coated porous gradient scaffold by polyphenol groups is constructed. The PDA-coated "hard" scaffolds promoted Ca2+ chelation and mineral deposition; the "soft" bioactive matrix is beneficial to the migration, proliferation, and osteogenic differentiation of stem cells in vitro, accelerated endogenous stem cell recruitment, and initiated rapid angiogenesis in vivo. The results of the rabbit cranial defect model (Φ = 10 mm) confirmed that BM-g-DPCL promoted the integration between bone tissue and implant and induced the deposition of bone matrix. Proteomics confirmed that cytokine adhesion, biomineralization, rapid vascularization, and extracellular matrix formation are major factors that accelerate bone defect healing. This strategy of highly chemically bonded soft-hard components guided the construction of the bioactive regenerative scaffold.

Design and validation of performance-oriented injectable chitosan thermosensitive hydrogels for endoscopic submucosal dissection.

Endoscopic submucosal dissection (ESD) is a challenging procedure. The use of biomaterials to improve the operator's convenience (operating affinity) has received little attention. We prepared two thermosensitive hydrogels, lactobionic acid-modified chitosan/chitosan/ß-glycerophosphate thermosensitive hydrogel (hydrogel 1) and its lyophilized powders (hydrogel 2), characterized their physicochemical properties and evaluated their performance in ESD experiments on large animals, by comparing with the commonly used normal saline (NS) and glycerin fructose (GF). These hydrogels showed good low-temperature fluidity; their viscosities at 4 °C were 92.2 mPa.s and 26.9 mPa.s, respectively. The hydrogels provided significantly better viscoelastic properties than NS and GF. The relaxation moduli of hydrogels were higher than those of NS and GF when the strains were 1 %, 5 %, and 10 %. The hydrogels can be maintained for seven days, even at pH 1, after which they degrade entirely. In pig model experiments, we performed submucosal injection and ESD procedures in the stomach and esophagus. The cushion height produced by the hydrogels was higher than those of NS and GF 30 min after injection. The ESD operation time for hydrogels was significantly shorter. Postoperative wound observation and histological analysis showed that the hydrogels promoted wound healing. The two hydrogels differed in fluidity, viscoelasticity, and other properties, which makes it possible to select the hydrogels according to the size and location of the lesion during ESD operation, and hydrogel 2 may be more suitable for use in lengthier procedures. In general, the hydrogels showed good performance, facilitated the intraoperative operation of ESD, shorten the operation time and promoted wound healing, which is of great significance for reducing the complications and reducing the threshold of ESD operation and further promoting the popularity of ESD.