Microenvironment-responsive bilayer hydrogel microspheres with gelatin-shell for osteoarthritis treatment.

Osteoarthritis is a long-term degenerative condition of the joints that is characterized by the breakdown of cartilage and inflammation of the synovial membrane. The presence of an inflammatory microenvironment and the degradation of the extracellular matrix produced by chondrocytes leads to the aggravation of cartilage injury, hindering the treatment of osteoarthritis. A promising approach to address this issue is to apply a combined strategy that is sensitive to the specific conditions in osteoarthritic joints and possesses properties that can reduce inflammation and promote cartilage healing. Here, inspired by the structure of chocolate-covered peanuts, we developed an injectable, environment-responsive bilayer hydrogel microsphere using microfluidics technology. The microsphere applied chondroitin sulfate methacryloyl (ChsMA) as its core and was coated with a methacryloyl gelatin (GelMA) shell that was loaded with celecoxib (CLX) liposomes (ChsMA+CLX@Lipo@GelMA). CLX was released from the liposomes when the GelMA shell rapidly degraded in response to the osteoarthritic microenvironment and suppressed the generation of inflammatory agents, demonstrating a beneficial impact of the outer shell in reducing inflammation. While the inner methacryloyl microsphere core degraded, chondroitin sulfate was released to promote chondrocyte anabolism and facilitate cartilage repair. Thus, the synthesized bilayer hydrogel microspheres hold great potential for treating osteoarthritis.

Alterations in phosphorus, calcium and PTHrP contribute to defects in dental and dental alveolar bone formation in calcium-sensing receptor-deficient mice.

To determine whether the calcium-sensing receptor (CaR) participates in tooth formation and dental alveolar bone development in mandibles in vivo, we examined these processes, as well as mineralization, in 2-week-old CaR-knockout (CaR(-/-)) mice. We also attempted to rescue the phenotype of CaR(-/-) mice by genetic means, in mice doubly homozygous for CaR and 25-hydroxyvitamin D 1alpha-hydroxylase [1alpha(OH)ase] or parathyroid hormone (Pth). In CaR(-/-) mice, which exhibited hypercalcemia, hypophosphatemia and increased serum PTH, the volumes of teeth and of dental alveolar bone were decreased dramatically, whereas the ratio of the area of predentin to total dentin and the number and surface of osteoblasts in dental alveolar bone were increased significantly, as compared with wild-type littermates. The normocalcemia present in CaR(-/-);1alpha(OH)ase(-/-) mice only slightly improved the defects in dental and alveolar bone formation observed in the hypercalcemic CaR(-/-) mice. However, these defects were completely rescued by the additional elimination of hypophosphatemia and by an increase in parathyroid hormone-related protein (PTHrP) expression in the apical pulp, Hertwig's epithelial root sheath and mandibular tissue in CaR(-/-); Pth(-/-) mice. Therefore, alterations in calcium, phosphorus and PTHrP contribute to defects in the formation of teeth and alveolar bone in CaR-deficient mice. This study indicates that CaR participates in the formation of teeth and in the development of dental alveolar bone in mandibles in vivo, although it appears to do so largely indirectly.

Surface bioengineering of diverse orthopaedic implants with optional functions via bioinspired molecular adhesion and bioorthogonal conjugations.

In this work, we reported an upgraded mussel-inspired strategy for surface bioengineering of osteoimplants by combination of mussel adhesion and bioorthogonal click chemistry. The main idea of this strategy is a mussel-inspired synthetic peptide containing multiple 3,4-dihydroxy-L-phenylalanine (DOPA) units and a dibenzocyclooctyne (DBCO) terminal (DOPA-DBCO). According to the mussel adhesion mechanism, the DOPA-DBCO peptide could stably adhere onto a variety of material surface, leaving the residual DBCO groups on the surface. Then, the DBCO residues could be employed for a second-step bioorthogonal conjugation with azide-capping biomolecules through bioorthogonal click chemistry, finally leading to the biomodified surfaces. To demonstrate the generality of our strategy for surface biomodification of diversified orthopaedic materials including metallic and polymeric substrates, we here conceptually conjugated some typical azide-capping biomolecules on both metal and polymeric surfaces. The results definitely verified the feasibility for engineering of functional surfaces with some essential requirements of osteoimplants, for example, the ability to facilitate cell adhesion, suppress bacterial infection, and promote osteogenesis. In a word, this study indicated that our novel surface strategy would show broad applicability for diverse osteoimplants and in different biological scenarios. We can also image that the molecular specificity of bioorthogonal conjugation and the universality of mussel adhesion mechanism may jointly provide a versatile surface bioengineering method for a wider range of biomedical implants.

Gelatin Templated Polypeptide Co-Cross-Linked Hydrogel for Bone Regeneration.

Polypeptides with short chains of amino acid monomers have been widely applied in the clinic because of their various biological functions. However, the easily-inactivated characteristics and burst releasing of the peptides limit their application in vivo. Here, a novel osteogenic polypeptide hydrogel (GelMA-c-OGP) is created by co-cross-linking template photo-cross-linked gelatin (GelMA) with photo-cross-linkable osteogenic growth peptides (OGP) using ultraviolet radiation. GelMA enables the formation of hydrogel with photo-cross-linkable OGP with good mechanical properties and also promotes bone regeneration. GelMA-c-OGP hydrogel accelerates the bone formation procedure of osteogenic precursor cells by significantly enhancing the expression of osteogenic-related genes BMP-2, OCN, and OPN, and increasing the precipitation of calcium salts in osteoblasts. Similarly, GelMA-c-OGP hydrogel promotes bone regeneration in vivo. Furthermore, it is observed that more collagen fibers connect cortical bones in the GelMA-c-OGP implanted group than the control group by hematoxylin-eosin and immunohistochemical staining of Collagen I and TGF-ß. The co-cross-linked OGP polypeptide converts from liquid to solid hydrogel with transient UV light in situ, which also can strengthen the mechanical property of the defect bone and avoid burst osteogenic peptide, releasing during the bone defect healing period. Overall, this hydrogel delivering system has a significant impact on bone defect healing compared with traditional methods.