Meta-analysis of the relationship between ocular and peripheral serum IL-17A and diabetic retinopathy.

Purpose: A systematic evaluation and Meta-analysis were performed to determine the relationship between IL-17A levels in ocular aqueous and peripheral venous serum samples and diabetic retinopathy (DR). Methods: PubMed, Embase, Web of Science, and CNKI databases were searched from the time of library construction to 2023-09-20.The results were combined using a random-effects model, sensitivity analyses were performed to determine whether the arithmetic was stable and reliable, and subgroup analyses were used to look for possible sources of heterogeneity. Results: A total of 7 case-control studies were included. The level of IL-17A was higher in the Nonproliferative DR(NPDR) group than in the Non-DR(NDR) group [SMD=2.07,95%CI(0.45,3.68),P=0.01], and the level of IL-17A in the proliferating DR(PDR) group was higher than that of the NDR group [SMD=4.66,95%CI(1.23,8.08),P<0.00001]. IL-17A levels in peripheral serum and atrial fluid were significantly higher in NPDR and PDR patients than in non-DR patients in subgroup analyses, and detection of peripheral serum IL-17A concentrations could help to assess the risk of progression from NPDR to PDR. Sensitivity analyses suggested that the results of the random-effects arithmetic were stable and reliable. Subgroup analyses based on assay method and sample source showed that the choice of these factors would largely influence the relationship between IL-17A levels and DR. Conclusion: Elevated peripheral serum and ocular aqueous humor IL-17A levels in diabetic patients are associated with the risk of DR, IL-17A may serve as a potential predictor or therapeutic target for DR, and IL-17A may be an important predictor of inflammation for the progression of NPDR to PDR. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024532900.

Spatiotemporal Modulated Scaffold for Endogenous Bone Regeneration via Harnessing Sequentially Released Guiding Signals.

The design of a scaffold that can regulate the sequential differentiation of bone marrow mesenchymal stromal cells (BMSCs) according to the endochondral ossification (ECO) mechanism is highly desirable for effective bone regeneration. In this study, we successfully fabricated a dual-networked composite hydrogel composed of gelatin and hyaluronic acid (termed GCDH-M), which can sequentially release chondroitin sulfate (CS) and magnesium/silicon (Mg/Si) ions to provide spatiotemporal guidance for chondrogenesis, angiogenesis, and osteogenesis. The fast release of CS is from the GCDH hydrogel, and the sustained releases of Mg/Si ions are from poly(lactide-co-glycolide) microspheres embedded in the hydrogel. There is a difference in the release rates between CS and ions, resulting in the ability for the fast release of CS and sustained release of ions. The dual networks between the modified gelatin and hyaluronic acid via covalent bonding and host-guest interactions render the hydrogel with some dynamic feature to meet the differentiation development of BMSCs laden inside the hydrogel, i.e., transforming into a chondrogenic phenotype, further to a hypertrophic phenotype and eventually to an osteogenic phenotype. As evidenced by the results of in vitro and in vivo evaluations, this GCDH-M composite hydrogel was proved to be able to create an optimal microenvironment for embedded BMSCs responding to the sequential guiding signals, which aligns with the rhythm of the ECO process and ultimately boosts bone regeneration. The promising outcome achieved with this innovative hydrogel system sheds light on novel scaffold design targeting bone tissue engineering.

Multileveled Hierarchical Hydrogel with Continuous Biophysical and Biochemical Gradients for Enhanced Repair of Full-Thickness Osteochondral Defect.

The repair of hierarchical osteochondral defect requires sophisticated gradient reestablishment; however, few strategies for continuous gradient casting consider the relevance to clinical practice regarding cell adaptability, multiple gradient elements, and precise gradient mirroring native tissue. Here, a hydrogel with continuous gradients in nano-hydroxyapatite (HA) content, mechanical, and magnetism is developed using synthesized superparamagnetic HA nanorods (MagHA) that easily respond to a brief magnetic field. To precisely reconstruct osteochondral tissue, the optimized gradient mode is calculated according to magnetic resonance imaging (MRI) of healthy rabbit knees. Then, MagHA are patterned to form continuous biophysical and biochemical gradients, consequently generating incremental HA, mechanical, and electromagnetic cues under an external magnetic stimulus. To make such depth-dependent biocues work, an adaptable hydrogel is developed to facilitate cell infiltration. Furthermore, this approach is applied in rabbit full-thickness osteochondral defects equipped with a local magnetic field. Surprisingly, this multileveled gradient composite hydrogel repairs osteochondral unit in a perfect heterogeneous feature, which mimics the gradual cartilage-to-subchondral transition. Collectively, this is the first study that combines an adaptable hydrogel with magneto-driven MagHA gradients to achieve promising outcomes in osteochondral regeneration.

Strategy of a cell-derived extracellular matrix for the construction of an osteochondral interlayer.

Osteochondral defects pose an enormous challenge due to the lack of an effective repair strategy. To tackle this issue, the importance of a calcified cartilage interlayer (CCL) in modulating osteochondral regeneration should be valued. Herein, we proposed that an extracellular matrix (ECM) derived from a suitable cell source might efficiently promote the formation of calcified cartilage. To the end, cell sheets from four kinds of cells, including bone marrow mesenchymal stem cells (BMSCs), pre-osteoblasts (MC3T3), chondrocytes (Cho), and artificially induced hypertrophic chondrocytes (HCho), were obtained by seeding the cells on electrospun fibrous meshes, followed by decellularization to prepare decellularized ECMs (D-ECMs) for BMSC re-seeding and differentiation studies. For cell proliferation, the BMSC-derived D-ECM exhibited the strongest promotion effect. For inducing the hypertrophic phenotype of re-seeded BMSCs, both the BMSC-derived and HCho-derived D-ECMs demonstrated stronger capacity in up-regulating the depositions of related proteins and the expressions of marker genes, as compared to the MC3T3-derived and Cho-derived D-ECMs. Accordingly, from the histological results of their subcutaneous implantation in rats, both the BMSC-derived and HCho-derived D-ECMs displayed obvious Masson's trichrome and Safranin-O/Fast-Green staining colors simultaneously, representing the characteristics related to osteogenesis and chondrogenesis. Differently, MC3T3-derived and Cho-derived D-ECMs were mainly detected during the osteogenic or chondrogenic expression, respectively. These findings confirmed that the BMSC-derived D-ECM could induce hypertrophic chondrocytes, though being a little inferior to the HCho-derived D-ECM. Overall, the BMSC-derived D-ECM could be a potential material in constructing the interlayer for osteochondral tissue engineering scaffolds to improve the regeneration efficiency.

Self-reinforcement hydrogel with sustainable oxygen-supply for enhanced cell ingrowth and potential tissue regeneration.

Hydrogels composed of natural biopolymers are attractive for tissue regeneration applications owing to their advantages such as biocompatibility and ease of administration, etc.. Yet, the low oxygen level and the crosslinked network inside bulk hydrogels, as well as the hypoxic status in defect areas, hamper cell viability, function, and eventual tissue repair. Herein, based on Ca2+-crosslinked alginate hydrogel, oxygen-generating calcium peroxide (CaO2) was introduced, which could provide a dynamic crosslinking alongside the CaO2 decomposition. Compared to the CaCl2-crosslinked alginate hydrogel, bone marrow mesenchymal stromal cells cultured with CaO2-contained system displayed remarkably improved biological behaviors. Furthermore, in vivo evaluations were carried out on a subcutaneous implantation in rats, and the results demonstrated the importance of the local oxygen availability in a series of crucial events for tissue regeneration, such as activating cell viability, migration, angiogenesis, and osteogenesis. In summary, the obtained Ca2+-crosslinked alginate hydrogel achieved a better microenvironment for cell ingrowth and potential tissue regeneration as the CaCl2 crosslinker being replaced by oxygen-generating CaO2 nanoparticles, due to its contribution in remedying the local hypoxic condition, promisingly, the release of Ca2+ makes the hydrogel to be a possible candidate scaffold for bone tissue engineering.

Controlled magnesium ion delivery system for in situ bone tissue engineering.

Magnesium cation (Mg2+) has been an emerging therapeutic agent for inducing vascularized bone regeneration. However, the therapeutic effects of current magnesium (Mg) -containing biomaterials are controversial due to the concentration- and stage-dependent behavior of Mg2+. Here, we first provide an overview of biochemical mechanism of Mg2+ in various concentrations and suggest that 2-10 mM Mg2+in vitro may be optimized. This review systematically summarizes and discusses several types of controlled Mg2+ delivery systems based on polymer-Mg composite scaffolds and Mg-containing hydrogels, as well as their design philosophy and several parameters that regulate Mg2+ release. Given that the continuous supply of Mg2+ may prevent biomineral deposition in the later stage of bone regeneration and maturation, we highlight the controlled delivery of Mg2+ based dual- or multi-ions system, especially for the hierarchical therapeutic ion release system, which shows enhanced biomineralization. Finally, the remaining challenges and perspectives of Mg-containing biomaterials for future in situ bone tissue engineering are discussed as well.

Mimicking osteochondral interface using pre-differentiated BMSCs/fibrous mesh complexes to promote tissue regeneration.

The heterogeneous nature of osteochondral tissue requires the construction of implant with biomimetic gradients. Electrospun fibrous meshes with different designs provide the feasibility in arranging such a kind of gradient structure via layer-by-layer stacking. In this study, a kind of triphasic implant was constructed by layering pre-differentiated cell sheets, which were hold by electrospun poly(L-lactide)/gelatin (PLLA/Gel) fibrous meshes containing hyaluronic acid and chondroitin sulfate for the cartilage layer or hydroxyapatite for the bone layer. As for the calcified interlayer, the bone marrow mesenchymal stromal cells (BMSCs) seeded on PLLA/Gel fibrous mesh was pre-differentiated with a mixed osteoinductive/chondroinductive (1:1) medium. With this gradient construct being implanted in rabbit knee osteochondral defect, it was found that both the cartilage and subchondral bone were regenerated effectively with reproduced tidal line structure. The importance of implants with biomimetic gradients for osteochondral defect repair was confirmed, and cell sheets on electrospun fibrous meshes were flexible for gradient structure construction via the layer-by-layer stacking technology. HighlightsComposite fibrous meshes with tissue-specific components are electrospun.Confluent BMSCs on fibrous meshes are chondrogenically or osteogenically induced.BMSCs hypertrophy is induced with the mixture of chondroinductive and osteoinductive medium.The pre-differentiated cell/mesh complexes are stacked layer-by-layer to form gradient construct.The gradient construct efficiently promotes osteochondral regeneration in rabbit joint.

The potential utility of hybrid photo-crosslinked hydrogels with non-immunogenic component for cartilage repair.

Finding a suitable biomaterial for scaffolding in cartilage tissue engineering has proved to be far from trivial. Nonetheless, it is clear that biomimetic approaches based on gelatin (Gel) and hyaluronic acid (HA) have particular promise. Herein, a set of formulations consisting of photo-polymerizable Gel; photo-polymerizable HA, and allogenic decellularized cartilage matrix (DCM), is synthesized and characterized. The novelty of this study lies particularly in the choice of DCM, which was harvested from an abnormal porcine with α-1,3-galactose gene knockout. The hybrid hydrogels were prepared and studied extensively, by spectroscopic methods, for their capacity to imbibe water, for their behavior under compression, and to characterize microstructure. Subsequently, the effects of the hydrogels on contacting cells (in vitro) were studied, i.e., cytotoxicity, morphology, and differentiation through monitoring the specific markers ACAN, Sox9, Coll2, and Col2α1, hypertrophy through monitoring the specific markers alkaline phosphatase (ALP) and Col 10A1. In vivo performance of the hydrogels was assessed in a rat knee cartilage defect model. The new data expand our understanding of hydrogels built of Gel and HA, since they reveal that a significant augmenting role can be played by DCM. The data strongly suggest that further experimentation in larger cartilage-defect animal models is worthwhile and has potential utility for tissue engineering and regenerative medicine.

Hydrogel composite scaffolds with an attenuated immunogenicity component for bone tissue engineering applications.

Xenogeneic bones are potential templates for bone regeneration. In this study, decellularized porcine bone powder with attenuated immunogenicity was incorporated into a photocurable hydrogel, gelatin methacryloyl (GelMA), to obtain scaffolds with good mechanical properties for bone tissue engineering. The decellularized bone powder (DCB)-GelMA hybrid scaffolds had higher compressive strength and stiffness values when the DCB content was increased. In vitro evaluations revealed the biocompatibility of these scaffolds. The scaffolds could induce human bone marrow mesenchymal stem cells (hMSCs) to undergo osteogenic differentiation even in the absence of an induction medium. The efficiency of the scaffolds for bone regeneration applications was further evaluated using an in vivo cranial bone defect model in rats. Micro-CT images showed that the hybrid scaffolds with 20% DCB content had the best effect in promoting new bone regeneration. Thus, it was concluded that the DCB-GelMA hybrid scaffolds have high potential in bone tissue engineering applications.

Lysozyme (Lys), Tannic Acid (TA), and Graphene Oxide (GO) Thin Coating for Antibacterial and Enhanced Osteogenesis.

Dental implants have great potential in the global market, around $3.7 billion in 2015, which will increase to $7 billion in 2023 with an annual increase rate of 8.2%. Incorporating antibacterial and osteogenic agents into implants is helpful to make the dental implants successful, which can be endowed by coatings. In recent years, graphene oxide (GO) and its composite materials have shown advances in the biomedical field. Lysozyme (Lys) and tannic acid (TA) are naturally derived, with promising antibacterial and osteogenic properties as well. In the present study, the strong antibacterial and enhanced osteogenic multilayer coating is fabricated using the facile and controllable layer by layer (LBL) technique to integrate GO, Lys, and TA. The thickness of coating exhibited a continuous growth with the deposited process as proved from UV-vis and ellipsometry data, and the physical properties of the coating, such as wettability, roughness, and stiffness are well characterized. The coatings exhibited the synergic effect on the killing bacteria, both Gram-negative bacteria and Gram-positive bacteria represented by E. coli and S. aureus, respectively, and enhancing osteogenesis of dental pulp stem cells (hDPSCs), showing the potential application on coatings of dental implants. Thus, the strategy applied here will inspire the design and development of dual functional surfaces for the success of implanted dental surface in future.

Graphene Oxide and Lysozyme Ultrathin Films with Strong Antibacterial and Enhanced Osteogenesis.

There is a great demand worldwide for bone-related implant materials. The drawbacks of chronic infections and poor bone healing of current implant materials have limited their clinical applications. Functionalizing the implant surfaces with antibacterial and osteogenic films on implant materials provides new opportunities for fabricating novel implant materials. In the present study, an ultrathin (GO/Lys)8 film of several tens of nanometers was fabricated using a layer-by-layer (LBL) technique with alternative deposition of graphene oxide (GO) and lysozyme (Lys). The deposition of the (GO/Lys) n film exhibited a successive growth as supported by ellipsometry, UV-vis, and Fourier transform infrared data, and the physical properties (morphology, roughness, and stiffness) of this film were characterized with an atomic force microscope. The ultrathin films exhibited a great effect on bacterium sterilization of Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli and enhanced osteogenic differentiation efficiency, showing the potential application in bone implant coatings. We believe that this LBL assembling strategy will pave the way for fabricating dual-functional surfaces and guide the design of the implanted surfaces in the future.

Directing osteogenic differentiation of BMSCs by cell-secreted decellularized extracellular matrixes from different cell types.

Cell-secreted decellularized extracellular matrixes (D-ECM) are promising for conferring bioactivity and directing cell fate to facilitate tissue regeneration. A cell sheet is a good shape for obtaining D-ECM after decellularization. In this study, cell sheets derived from bone marrow mesenchymal stem cells (BMSCs), MC3T3 osteoblasts, and L929 fibroblasts were decellularized, the three types of D-ECMs obtained were investigated for their capabilities in inducing osteogenic differentiation of re-seeded BMSCs. The D-ECMs were found to be rich in collagen and glycosaminoglycan, at the same time, showing the presence of growth factors, such as vascular endothelial growth factor and bone morphogenetic protein. These all supported the proliferation of BMSCs well, however, they influenced the osteogenic differentiation of BMSCs to different extents. The D-ECM prepared from the BMSC sheet was found to promote the osteogenic differentiation of re-seeded BMSCs the most in vitro, as well as displaying the potential to induce ectopic osteogenesis when being subcutaneously implanted. The results suggested that D-ECMs would be promising for bone tissue engineering applications, however, they favored osteogenesis to different extents, which was closely related to the cell types.

Guided bone regeneration with asymmetric collagen-chitosan membranes containing aspirin-loaded chitosan nanoparticles.

INTRODUCTION: Membranes allowing the sustained release of drugs that can achieve cell adhesion are very promising for guided bone regeneration. Previous studies have suggested that aspirin has the potential to promote bone regeneration. The purpose of this study was to prepare a local drug delivery system with aspirin-loaded chitosan nanoparticles (ACS) contained in an asymmetric collagen-chitosan membrane (CCM). METHODS: In this study, the ACS were fabricated using different concentrations of aspirin (5 mg, 25 mg, 50 mg, and 75 mg). The drug release behavior of ACS was studied. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were used to examine the micromorphology of ACS and aspirin-loaded chitosan nanoparticles contained in chitosan-collagen membranes (ACS-CCM). In vitro bone mesenchymal stem cells (BMSCs) were cultured and critical-sized cranial defects on Sprague-Dawley rats were made to evaluate the effect of the ACS-CCM on bone regeneration. RESULTS: Drug release behavior results of ACS showed that the nanoparticles fabricated in this study could successfully sustain the release of the drug. TEM showed the morphology of the nanoparticles. SEM images indicated that the asymmetric membrane comprised a loose collagen layer and a dense chitosan layer. In vitro studies showed that ACS-CCM could promote the proliferation of BMSCs, and that the degree of differentiated BMSCs seeded on CCMs containing 50 mg of ACS was higher than that of other membranes. Micro-computed tomography showed that 50 mg of ACS-CCM resulted in enhanced bone regeneration compared with the control group. CONCLUSION: This study shows that the ACS-CCM would allow the sustained release of aspirin and have further osteogenic potential. This membrane is a promising therapeutic approach to guiding bone regeneration.