Dissolving Hyaluronic Acid-Based Microneedles to Transdermally Deliver Eugenol Combined with Photothermal Therapy for Acne Vulgaris Treatment.

A microneedle transdermal drug delivery system simultaneously avoids systemic toxicity of oral administration and low efficiency of traditional transdermal administration, which is of great significance for acne vulgaris therapy. Herein, eugenol-loaded hyaluronic acid-based dissolving microneedles (E@P-EO-HA MNs) with antibacterial and anti-inflammatory activities are developed for acne vulgaris therapy via eugenol transdermal delivery integrated with photothermal therapy. E@P-EO-HA MNs are pyramid-shaped with a sharp tip and a hollow cavity structure, which possess sufficient mechanical strength to penetrate the stratum corneum of the skin and achieve transdermal delivery, in addition to excellent in vivo biocompatibility. Significantly, E@P-EO-HA MNs show effective photothermal therapy to destroy sebaceous glands and achieve antibacterial activity against deep-seated Propionibacterium acnes (P. acnes) under near-infrared-light irradiation. Moreover, cavity-loaded eugenol is released from rapidly dissolved microneedle bodies to play a sustained antibacterial and anti-inflammatory therapy on the P. acnes infectious wound. E@P-EO-HA MNs based on a synergistic therapeutic strategy combining photothermal therapy and eugenol transdermal administration can significantly alleviate inflammatory response and ultimately facilitate the repair of acne vulgaris. Overall, E@P-EO-HA MNs are expected to be clinically applied as a functional minimally invasive transdermal delivery strategy for superficial skin diseases therapy in skin tissue engineering.

Cell softness reveals tumorigenic potential via ITGB8/AKT/glycolysis signaling in a mice model of orthotopic bladder cancer.

BACKGROUND: Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a micro-barrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells. METHODS: The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin ß8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. RESULTS: Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts. CONCLUSIONS: The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

How do intellectual property demonstration cities contribute to low-carbon development? Evidence from China.

An intellectual property demonstration city (IPDC) not only promotes innovation, but also brings many unexpected gains, the most prominent of which is carbon reduction. Unfortunately, few scholars have included IPDC and carbon emissions in a unified research framework, ignoring the role of intellectual property protection in environmental governance. Therefore, this paper investigates the impact of IPDC on carbon emissions through a multi-period difference-in-difference (DID) model, a spatial DID model, and a mediating effect model with IPDC policy as a quasi-natural experiment. The research results are as follows: (1) IPDC policy has a significant inhibitory effect on carbon emissions. Compared to non-pilot cities, IPDC policy can reduce carbon emissions by about 20.6%. (2) There are temporal and regional heterogeneity of the IPDC policy on carbon emissions. More specifically, the carbon reduction effect of IPDC is more effective in large cities and cities with richer human capital, stricter environmental regulation, and higher financial development. Meanwhile, the policy effects in 2012 and 2015 are larger than those in 2018, while the policy effects in 2014, 2016, and 2019 are not significant. (3) IPDC policy reduces carbon emissions mainly by stimulating innovation and green innovation, and promoting R&D element agglomeration. (4) IPDC policy has obvious spatial spillover effects and leads to the surrounding cities becoming pollution havens. The above conclusions have implications for designing a better urbanization model to promote innovative development and reduce carbon emissions.

Extracellular matrix-derived mechanical force governs breast cancer cell stemness and quiescence transition through integrin-DDR signaling.

The extracellular matrix (ECM) serves as signals that regulate specific cell states in tumor tissues. Increasing evidence suggests that extracellular biomechanical force signals are critical in tumor progression. In this study, we aimed to explore the influence of ECM-derived biomechanical force on breast cancer cell status. Experiments were conducted using 3D collagen, fibrinogen, and Matrigel matrices to investigate the role of mechanical force in tumor development. Integrin-cytoskeleton-AIRE and DDR-STAT signals were examined using RNA sequencing and western blotting. Data from 1358 patients and 86 clinical specimens were used for ECM signature-prognosis analysis. Our findings revealed that ECM-derived mechanical force regulated tumor stemness and cell quiescence in breast cancer cells. A mechanical force of ~45 Pa derived from the extracellular substrate activated integrin ß1/3 receptors, stimulating stem cell signaling pathways through the cytoskeleton/AIRE axis and promoting tumorigenic potential and stem-like phenotypes. However, excessive mechanical force (450 Pa) could drive stem-like cancer cells into a quiescent state, with the removal of mechanical forces leading to vigorous proliferation in quiescent cancer stem cells. Mechanical force facilitated cell cycle arrest to induce quiescence, dependent on DDR2/STAT1/P27 signaling. Therefore, ECM-derived mechanical force governs breast cancer cell status and proliferative characteristics through stiffness alterations. We further established an ECM signature based on the fibrinogen/fibronectin/vitronectin/elastin axis, which efficiently predicts patient prognosis in breast cancer. Our findings highlight the vital role of ECM-derived mechanical force in governing breast cancer cell stemness/quiescence transition and suggest the novel use of ECM signature in predicting the clinical prognosis of breast cancer.

Antibacterial Conductive Collagen-Based Hydrogels for Accelerated Full-Thickness Wound Healing.

Antibacterial conductive hydrogels have been extensively utilized in tissue repair and regeneration on account of their unique electrochemical performances and advantages of anti-pathogenic bacterial infection. Here, multi-functional collagen-based hydrogels (CHLY) with adhesivity, conductivity, and antibacterial and antioxidant activities were developed by introducing cysteine-modified ε-poly(l-lysine) (ε-PL-SH) and in situ-polymerized polypyrrole (PPy) nanoparticles to induce full-thickness wound healing. CHLY hydrogels have a low swelling ratio, good compressive strength, and viscoelasticity due to chemical crosslinking, chelation, physical interaction, and nano-reinforcements in the matrix network of hydrogels. CHLY hydrogels possess excellent tissue adhesion ability, low cytotoxicity, enhanced cell migration ability, and good blood coagulation performance without causing hemolysis. Interestingly, the chemical conjugation of ε-PL-SH in the hydrogel matrix gives hydrogels an inherently robust and broad-spectrum antibacterial activity, while the introduction of PPy endows hydrogels with superior free radical scavenging capacity and good electroactivity. Significantly, CHLY hydrogels have advantages in alleviating persistent inflammatory response as well as promoting angiogenesis, epidermis regeneration, and orderly collagen deposition at the wound sites through their multi-functional synergies, thus effectively accelerating full-thickness wound healing and improving wound healing quality. Overall, our developed multi-functional collagen-based hydrogel dressing demonstrates promising application prospects in the field of tissue engineering to induce skin regeneration.

Dual-drug loaded polysaccharide-based self-healing hydrogels with multifunctionality for promoting diabetic wound healing.

Diabetic chronic wound healing still faces huge clinical challenge. The arrangement and coordination of healing processes are disordered in diabetic wound caused by the persistent inflammatory response, microbial infection, impaired angiogenesis, resulting in the delayed and even non-healing wounds. Here, the dual-drug loaded nanocomposite polysaccharide-based self-healing hydrogels (OCM@P) with multifunctionality were developed to promote diabetic wound healing. Curcumin (Cur) loaded mesoporous polydopamine nanoparticles (MPDA@Cur NPs) and metformin (Met) were introduced into the polymer matrix formed by the dynamic imine bonds and electrostatic interactions between carboxymethyl chitosan and oxidized hyaluronic acid to fabricate OCM@P hydrogels. OCM@P hydrogels show homogeneous and interconnected porous microstructure, which possess good tissue adhesiveness, enhanced compression strength, great anti-fatigue behavior, excellent self-recovery capacity, low cytotoxicity, rapid hemostatic ability and robust broad-spectrum antibacterial activity. Interestingly, OCM@P hydrogels exhibit rapid release of Met and long-term sustained release of Cur, thereby to effectively scavenge extracellular and intracellular free radicals. Significantly, OCM@P hydrogels remarkably promote re-epithelization, granulation tissue formation, collagen deposition and arrangement, angiogenesis as well as wound contraction in diabetic wound healing. Overall, the multifunctional synergy of OCM@P hydrogels greatly contributes to accelerating diabetic wound healing, which demonstrate promising application as scaffolds in regenerative medicine.

Antibacterial Collagen-Based Nanocomposite Dressings for Promoting Infected Wound Healing.

Pathogenic bacterial infection is the most frequent wound complication, which has become a major clinical and healthcare challenge in wound management worldwide, leading to impaired healing processes, the risk of amputation, and even death. Here, collagen-based nanocomposite dressings (APZC) with broad-spectrum antibacterial activity are developed to promote the infected full-thickness wound healing. Short rod-like shaped ZnO NPs are synthesized and then coated with polydopamine (PDA) to obtain PDA coated ZnO NPs (PDA@ZnO NPs). Afterward, PDA@ZnO NPs are conjugated on the backbone of a collagen chain, and the obtained collagen-PDA@ZnO NPs conjugate is crosslinked by dialdehyde sodium alginate to fabricate APZC dressings. PDA@ZnO NPs show well dispersibility and are uniformly incorporated into the collagen matrix. APZC dressings have interconnected microporous structure and great physicochemical properties, besides good blood coagulation performance and well cytocompatibility. APZC dressings demonstrate long-lasting and excellently broad-spectrum antimicrobial activity, which can relieve the inflammatory reaction by killing pathogenic bacteria and induce the generation of blood vessels and the orderly deposition of collagen in the wound site, thus promoting infected full-thickness wound healing without obvious scar formation. Overall, the functionalized collagen-based nanocomposite dressings have great potential in the clinical treatment against bacteria-associated wound infection.

Gelatin/alginate-based microspheres with sphere-in-capsule structure for spatiotemporal manipulative drug release in gastrointestinal tract.

Microsphere with sphere-in-capsule structure is a multi-drugs delivery system to achieve the purpose of combination therapy. In this paper, we have prepared gelatin/alginate-based microspheres with sphere-in-capsule structure by a relatively fast, simple, and easily large-scale industrialized emulsification method for spatiotemporal manipulative drug release in gastrointestinal tract. Calcium alginate microspheres encapsulated with bovine serum albumin (BSA) were first prepared as inner microspheres, and then inner microspheres and ranitidine hydrochloride (RH) were co-encapsulated by gelatin microspheres to form double-layer microspheres with sphere-in-capsule structure. The size and distribution of microspheres can be easily controlled by emulsifying conditions. The microspheres with sphere-in-capsule structure displayed desirable encapsulation efficiency of BSA (61.52 %) and RH (56.07 %). The in vitro simulated drug release showed the spatiotemporal release feature of microspheres with sphere-in-capsule structure. In the specific simulated fluid, the release behavior and cumulative release of RH (sustainedly released 95 % in simulated gastric fluid) and BSA (rapidly released 73 % in simulated intestinal fluid) were different. The drug release mechanisms were analyzed to determine RH and BSA's release behavior. Overall, the microspheres with sphere-in-capsule structure have the potential application of spatiotemporal manipulative drug delivery in the gastrointestinal tract.

Multifunctional ß-Cyclodextrin-Poly(ethylene glycol)-Cholesterol Nanomicelle for Anticancer Drug Delivery.

Nanoparticle drug delivery systems have drawn considerable attention worldwide due to their unique characteristics and advantages in anticancer drug delivery. Herein, the curcumin (Cur) loaded nanomicelles with two-stage drug release behavior were developed. ß-Cyclodextrin (ß-CD) and cholesterol were conjugated onto both ends of the poly(ethylene glycol) (PEG) chain to obtain an amphiphilic ß-CD-PEG-Chol. The Cur was loaded into the cavities of ß-CD and nanomicelle when the ß-CD-PEG-Chol self-assembled to the Cur@ß-CD-PEG-Chol nanomicelles (Cur@CPC NMs). These Cur@CPC NMs are spherical particles with a particle size of 120.9 nm. The Cur drug loading capacity of Cur@CPC NMs are 61.6 ± 6.9 mg/g. The release behavior of Cur from Cur@CPC NMs conformed to a two-stage mode of "burst-release followed by sustained-release". The prepared Cur@CPC NMs possess high storage stability and excellent hemocompatibility. Moreover, these Cur@CPC NMs exhibit satisfactory antioxidant activity and anticancer activity, resulting in significant reduction in intracellular H2O2-induced ROS and a nearly 50% lethality rate of HepG-2 cells. Meanwhile, the Cur@CPC NMs show good anti-inflammatory activity, by which the secretion of inflammatory factors of IL-6 and TNF-α are inhibited. Overall, the developed Cur@CPC NMs show application prospects in anticancer drug delivery systems.

Does Eco-Compensation Alleviate Rural Poverty? New Evidence from National Key Ecological Function Areas in China.

The Transfer Payment Policy of National Key Ecological Functional Areas (TPEFAP), a well-known ecological compensation (eco-compensation) scheme in China, has been proposed by the government to alleviate ecological poverty and protect the environment. In literature, the effectiveness of the TPEFAP on environmental conservation has been widely examined, while few pay attention to the effect of the TPEFAP on poverty alleviation, especially with the consideration of its spatial spillovers as well. In this paper, we utilize panel data covering the key ecological functional areas of China during the period 2011-2018 to evaluate the impact of the TPEFAP on poverty alleviation and also its spatial spillovers by employing the synthetic control method (SCM) and the dynamic spatial Durbin model, respectively. Specifically, we apply the entropy weight method (EWM) to calculate the multidimensional poverty index (MPI) and measure pro-poor effect in terms of MPI change. The results show that: (1) TPEFAP has stable positive effects on MPI in Hubei, Yunnan, Jilin, Gansu, and Ningxia, while the impact on Qinghai fluctuates. (2) MPI presents a significant spatial correlation. Furthermore, both the direct and indirect effects of TPEFAP on MPI are significant and stable positive, for both short- or long-term. (3) For potential channels, rural non-farm employment, rural labor mobility, and agricultural productivity are the key pathways through which the TPEFAP can alleviate poverty both in local and adjacent provinces. However, it is difficult to find significant positive spatial spillovers for the TPEFAP if only the natural resources scale is considered. This study indicates that the government should pay attention to the policy expectations of ecological poverty alleviation and, in future eco-compensation, must further increase the coverage of subsidies and diversify the forms of subsidies.

Matrix metalloproteinase-responsive collagen-oxidized hyaluronic acid injectable hydrogels for osteoarthritic therapy.

Drug delivery system and intra-articular injection have been clinically applied to prolong drug residence time and reduce side effects in the treatment of osteoarthrosis. Herein, injectable hydrogels with sustained-dexamethasone sodium phosphate (DSP) release behavior in response to matrix metalloproteinase (MMP) were developed for osteoarthritic therapy. Hyaluronic acid undergoes specific oxidation in the present of sodium periodate to prepare oxidized hyaluronic acid (OHA). Then the DSP-loaded collagen-based hydrogels (Col-OHA) were developed by the Schiff's base crosslinking between OHA and Type I collagen besides the self-assembly of collagen induced by OHA. The results indicate that the collagen self-assembly into collagen fibrils makes great contribution for shortening gelation time of Col-OHA hydrogels. Col-OHA hydrogels possess interconnected porous microstructure, good injectability, excellent self-healing performance, strong mechanical property, low swelling ability, good blood compatibility and no cytotoxicity. Significantly, Col-OHA hydrogels show highly sensitive and significantly substantially sustained release of DSP in response to MMP. DSP-loaded Col-OHA hydrogel possesses significant inhibition for the production of inflammatory cytokines in the joint synovium, which can effectively relieve the symptoms of osteoarthritis continuously. Col-OHA hydrogel has no obvious effect on liver and kidney functions. Overall, the Col-OHA hydrogels with excellent biocompatibility are the promising drug-loading system for the intra-articular injection therapy of osteoarthrosis.

Blockade of integrin signaling reduces chemotherapy-induced premature senescence in collagen cultured bladder cancer cells.

Background: Diminished sensitivity towards chemotherapy remains the major impediment to the clinical treatment of bladder cancer. However, the critical elements in control of chemotherapy resistance remain obscure. Methods: We adopted improved collagen gels and performed cytotoxicity analysis of doxorubicin (DOX) and mitomycin C (MMC) of bladder cancer cells in a 3D culture system. We then detected the expression of multidrug resistant gene ABCB1, dormancy-associated functional protein chicken ovalbumin upstream-transcription factor 1 (COUPTF1), cell proliferation marker Ki-67, and cellular senescence marker senescence-associated ß-galactosidase (SA-ß-Gal) in these cells. We further tested the effects of integrin blockade or protein kinase B (AKT) inhibitor on the senescent state of bladder cancer. Also, we examined the tumor growth and survival time of bladder cancer mouse models given the combination treatment of chemotherapeutic agents and integrin α2ß1 ligand peptide TFA (TFA). Results: Collagen gels played a repressive role in bladder cancer cell apoptosis induced by DOX and MMC. In mechanism, collagen activated the integrin ß1/AKT cascade to drive bladder cancer cells into a premature senescence state via the p21/p53 pathway, thus attenuating chemotherapy-induced apoptosis. In addition, TFA had the ability to mediate the switch from senescence to apoptosis of bladder cancer cells in xenograft mice. Meanwhile, TFA combined with chemotherapeutic drugs produced a substantial suppression of tumor growth as well as an extension of survival time in vivo. Conclusions: Based on our finding that integrin ß1/AKT acted primarily to impart premature senescence to bladder cancer cells cultured in collagen gel, we suggest that integrin ß1 might be a feasible target for bladder cancer eradication.

131I-Labeled Silk Fibroin Microspheres for Radioembolic Therapy of Rat Hepatocellular Carcinoma.

Transarterial radioembolization (TARE) is a promising technology in hepatocellular carcinoma (HCC) therapy, which utilizes radionuclide-labeled microspheres to achieve arterial embolization and internal irradiation. However, the therapeutic effect of liver cancer can be affected by low radionuclide labeling rate and stability, as well as poor biocompatibility, and non-biodegradability of microspheres. Here, 131I-labeled silk fibroin microspheres (131I-SFMs) were developed as radioembolization material for effective TARE therapy against HCC. Silk fibroin rich in 10.03% of tyrosine was extracted from silkworm cocoons and then emulsified and genipin-crosslinked to prepare SFMs. SFMs show a good settlement rate, biodegradability, hemocompatibility, and low cytotoxicity. Afterward, 131I-SFMs were obtained by radiolabeling 131I onto the SFMs through the chloramine-T method. 131I-SFMs possess a high 131I labeling rate of over 84% and good radioactive stability and are thus conducive to internal radiotherapy. Significantly, 131I-SFMs with diameters around 11 µm were successfully radioembolized at the hepatic artery. 131I-SFMs were diffused in the liver, indicating the favorable biodistribution and biosafety in vivo. Based on the combination of embolization and local radiotherapy, the administration of 131I-SFMs shows a favorable inhibitive effect against the progression of HCC. Overall, the newly developed 131I-SFMs as radioembolization microspheres provide a promising application for effective TARE therapy against liver cancer.

Antibacterial dialdehyde sodium alginate/ε-polylysine microspheres for fruit preservation.

Food security is an important global public health issue, which will not only endanger consumers' life and health, but also cause serious food waste. Herein, antibacterial dialdehyde sodium alginate/ε-polylysine microspheres (DSA-PL MPs) were developed to effectively prolong the shelf life of fruit. DSA was prepared by periodate oxidation of sodium alginate. Then the PL was conjugated onto DSA backbone via the Schiff's base reaction to synthesize DSA-PL conjugates, followed by the emulsification and Ca2+ ions crosslinking to obtain DSA-PL MPs. The results indicate that DSA-PL MPs show smooth spherical particle, relatively narrow size distribution and good dispersity. In vitro degradation rate of DSA-PL MPs is higher in acetate buffer (pH = 5.0) than that in PBS buffer (pH = 7.4), showing acid-sensitive degradation property. Significantly, DSA-PL MPs possess strong broad-spectrum antibacterial activity, which can effectively extend the shelf life of fruit. Overall, DSA-PL MPs possess promising application as antibacterial agents for fruit preservation.

Crosslinking effect of dialdehyde cholesterol modified starch nanoparticles on collagen hydrogel.

Crosslinking is frequently used to improve the inherent poor physicochemical properties of collagen. However, local flocculation and irregular crosslinking of collagen would be unavoidably occurred once contacting with crosslinking agents due to widespread complex interactions. Herein, dialdehyde starch-based nanoparticles were developed to crosslink collagen as a new strategy. Starch was conjugated with cholesterol chloroformate before periodate oxidation to obtain dialdehyde cholesterol modified starch (DACS). DACS self-assembled into nanoparticles (DACSNPs) and crosslinked with collagen to fabricate collagen hydrogels (DACSNPs-Col). DACSNPs-Col hydrogels exhibited faster gelation rate, better uniform porous structure, higher mechanical properties and better degradation stability than dialdehyde starch crosslinked hydrogels. Significantly, DACSNPs-Col hydrogels show homogeneous structure, improved mechanical properties, low cytotoxicity, well blood compatibility, high cell adhesion and proliferation. Overall, the oxidized polysaccharide nanoparticles crosslinked collagen hydrogels have homogeneous and compact microstructure and improved physicochemical properties, which show potential application prospect in the field of tissue engineering scaffold.

Policy shock effect of SDP on environmental total factors productivity: 53 coal cities versus 165 non-resource-based cities.

The trend of economic decline for coal cities is a serious threat to the high-quality development of China's economy, and how to improve the environmental total factor productivity (ETFP) has become an urgent issue. Based on the framework of data envelopment analysis (DEA), this paper estimates ETFP using the global Malmquist-Luenberger productivity index (GMLPI). We decompose GMLPI into environmental technical efficiency change (ETEC) and the best practice gap change (BPGC). Then, the difference-in-difference (DID) model combining propensity score matching (PSM) method is used to investigate the effect of the Sustainable Development Plan of National Resource-based Cities (2013-2020) (SDP) aiming to improve ETFP. The results indicate that (1) On average, the GMLPI and BPGC are rising, while the ETEC is decreasing in the observed sample period; the western regions have the biggest BPGC, while the eastern regions have the biggest ETEC; (2) The SDP significantly improves the GMLPI and BPGC but has little effect on the ETEC; Coal cities located in eastern and central regions have policy effect, while the western regions do not have. (3) The SDP affects ETFP through slowing down the economic growth rate and reducing population agglomeration, but promoting the optimization of industrial structure. Those findings have policy implications for improving ETFP and promoting the industrial upgrade of coal cities.

Mimicking the Composition and Structure of the Osteochondral Tissue to Fabricate a Heterogeneous Three-Layer Scaffold for the Repair of Osteochondral Defects.

Heterogeneous three-layer scaffolds were fabricated by mimicking the biochemical composition and structure of the hyaline cartilage, calcified cartilage, and subchondral bone of the osteochondral tissue for the repair of osteochondral defects. The hyaline cartilage layer was composed of collagen I (50.0 wt %) and sodium hyaluronate (50.0 wt %). The calcified cartilage layer and subchondral bone layer were composed of collagen I, sodium hyaluronate, and nanohydroxyapatite with different proportions. N-Hydroxysuccinimide/N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride was used to mediate the crosslinking reaction of the amine groups of collagen with carboxyl groups of sodium hyaluronate. The hyaline cartilage layer and calcified cartilage layer were designed as dense structures, while the subchondral bone layer was designed as a relatively loose structure by adjusting the crosslinking degree. The scaffolds displayed a uniform and interconnected porous structure and possessed a high porosity over 85%, which were conducive to cellular adhesion and proliferation. The scaffolds could remain at 50-75% after 30 days of degradation owing to crosslinking, providing enough time for the regeneration of the osteochondral tissue. Especially, the hyaline cartilage layer and calcified cartilage layer preferred to induce the proliferation of chondrocytes, while the subchondral bone layer was more conducive to the proliferation of osteoblasts. In conclusion, the heterogeneous multilayer scaffolds could serve as implant materials for osteochondral reconstruction.

Fabrication of oxidized sodium alginate-collagen heterogeneous bilayer barrier membrane with osteogenesis-promoting ability.

Guided bone regeneration technique is an effective approach to repair bone defects, in which a barrier membrane is essential. However, the collagen barrier membranes commonly used lose stability quickly, leading to connective tissue invasion and failure of osteogenesis. Herein, we presented an oxidized sodium alginate (OSA)-collagen heterogeneous bilayer barrier membrane with well-controlled pore size and osteogenesis-promoting ability. The OSA crosslinking significantly improved the structural stability, compressive strength, swelling behavior, and slowed down the biodegradation rate of collagen membranes. Meanwhile, the collagen-based membranes exhibited superior cytocompatibility, osteogenesis-promotion, and barrier function against fibroblasts. Especially, the osteogenic differentiation was most promoted on the membrane with a large pore size (240-310 µm), while the barrier function was most improved on the membrane with a small pore size (30-60 µm). Then the above two membranes were combined together to obtain a heterogeneous bilayer membrane. This bilayer barrier membrane showed excellent osteogenesis-promoting ability in rats.