High performance injectable Mg doped bioactive glass bone cement for the regulation of osteogenic immune microenvironment.

Although calcium phosphate has been extensively utilized in orthopedic applications such as spine, limbs, dentistry, and maxillofacial surgery, the lack of osteoinductive properties often hinders its effectiveness in treating bone defects resulting from pathological micro-environment such as tumor surgery, osteoporosis, osteomyelitis, and diabetic. Therefore, a novel bone cement based on magnesium-doped bioactive glass was developed in this study. The moderate release of magnesium ions improved the mechanical properties by controlling the crystal size of hydroxyapatite. Through detailed discussion of element content and heat treatment temperature, it was found that 2Mg-BG-800 was suitable for the construction of bone cement. 2Mg-BG-BC exhibited favorable initial (15 min) and final (30 min) setting time, compressive strength (29.45 MPa), compressive modulus (1851.49 MPa), injectability, and shape-adaptability. Furthermore, Mg-BG-BC demonstrated the ability to enhance the osteogenic differentiation of BMSCs, and induce macrophage polarization towards the M2 phenotype, suggesting its potential for osteoporotic fracture regeneration.

Injectable and tissue adhesive EGCG-laden hyaluronic acid hydrogel depot for treating oxidative stress and inflammation.

Oxidative stress and inflammation are common pathological mechanisms for the progression of tissue degeneration. Epigallocatechin-3-gallate (EGCG) features antioxidant and anti-inflammatory properties, which is a promising drug for the treatment of tissue degeneration. Herein, we utilize the phenylborate ester reaction of EGCG and phenylboronic acid (PBA) to fabricate an injectable and tissue adhesive EGCG-laden hydrogel depot (EGCG HYPOT), which can achieve anti-inflammatory and antioxidative effects via smart delivery of EGCG. Specifically, the phenylborate ester bonds, formed by EGCG and PBA-modified methacrylated hyaluronic acid (HAMA-PBA), endow EGCG HYPOT injectability, shape adaptation and efficient load of EGCG. After photo-crosslinking, EGCG HYPOT exhibits good mechanical properties, tissue adhesion and sustained acid-responsive release of EGCG. EGCG HYPOT can scavenge oxygen and nitrogen free radicals. Meanwhile, EGCG HYPOT can scavenge intracellular reactive oxygen species (ROS) and suppress the expression of pro-inflammatory factors. EGCG HYPOT may provide a new idea for alleviation of inflammatory disturbance.

Assembling Microgels via Dynamic Cross-Linking Reaction Improves Printability, Microporosity, Tissue-Adhesion, and Self-Healing of Microgel Bioink for Extrusion Bioprinting.

Extrusion bioprinting has been widely used to fabricate complicated and heterogeneous constructs for tissue engineering and regenerative medicine. Despite the remarkable progress acquired so far, the exploration of qualified bioinks is still challenging, mainly due to the conflicting requirements on the printability/shape-fidelity and cell viability. Herein, a new strategy is proposed to formulate a dynamic cross-linked microgel assembly (DC-MA) bioink, which can achieve both high printability/shape-fidelity and high cell viability by strengthening intermicrogel interactions through dynamic covalent bonds while still maintaining the relatively low mechanical modulus of microgels. As a proof-of-concept, microgels are prepared by cross-linking hyaluronic acid modified with methacrylate and phenylboric acid groups (HAMA-PBA) and methacrylated gelatin (GelMA) via droplet-based microfluidics, followed by assembling into DC-MA bioink with a dynamic cross-linker (dopamine-modified hyaluronic acid, HA-DA). As a result, 2D and 3D constructs with high shape-fidelity can be printed without post-treatment, and the encapsulated L929 cells exhibit high cell viability after extrusion. Moreover, the addition of the dynamic cross-linker (HA-DA) also improves the microporosity, tissue-adhesion, and self-healing of the DC-MA bioink, which is very beneficial for tissue engineering and regenerative medicine applications including wound healing. We believe the present work sheds a new light on designing new bioinks for extrusion bioprinting.

Electrospun poly(3-hydroxybutyrate-co-4-hydroxybutyrate) /Octacalcium phosphate Nanofibrous membranes for effective guided bone regeneration.

Membranes used in guided bone regeneration (GBR) are required to exhibit high mechanical strength, biocompatibility, biodegradation, osteogenic and osteoinductive potential. In our study, poly(3-hydroxybutyrate-co-4-hydroxybutyrate)(P(3HB-co-4HB))/octacalcium phosphate (OCP) (P(3HB-co-4HB)/OCP) nanofibrous membranes were fabricated by electrospinning with two different P(3HB-co-4HB) to OCP ratios (P(3HB-co-4HB):OCP = 95:5 wt% and 90:10 wt%, termed P(3HB-co-4HB)/OCP(5)and P(3HB-co-4HB)/OCP (10), respectively) for GBR. The developed P(3HB-co-4HB)/OCP nanofibrous membranes were analysed for their osteogenic and osteoinductive properties using mesenchymal stem cells (MSCs) in vitro and in a calvarial bone defect rat model. The composite P(3HB-co-4HB)/OCP nanofibrous membranes showed decreased fibre size and enhanced tensile strength compared with those of P(3HB-co-4HB) nanofibrous membranes. In the in vitro studies, the P(3HB-co-4HB)/OCP membranes facilitated cell growth and osteoblastic differentiation of MSCs and were superior to P(3HB-co-4HB) membranes. After covered on the calvarial bone defects, P(3HB-co-4HB)/OCP membranes facilitated greater neobone formation than P(3HB-co-4HB) membranes did, as the result of histological evaluation and micro-CT analysis with higher bone volume/total volume (BV/TV) ratio and bone mineral density (BMD). P(3HB-co-4HB)/OCP(10) membranes with higher OCP content showed greater stiffness and osteoinductivity than P(3HB-co-4HB)/OCP (5)membranes, demonstrating the role of OCP in the composite membranes. These results indicated that electrospun P(3HB-co-4HB)/OCP nanofibrous membranes hold promise for the clinical application of GBR.

Electrospun PLGA/PCL/OCP nanofiber membranes promote osteogenic differentiation of mesenchymal stem cells (MSCs).

Nanofibers as niche-biomimetic scaffolds hold promise in guided bone regeneration (GBR). Here we fabricated poly (lactic-co-glycolic acid) (PLGA)/poly(caprolactone) (PCL)-doped octacalcium phosphate (OCP) nanofiber membranes via electrospinning and investigated the osteogenic behavior of marrow mesenchymal stem cells (MSCs) on the membranes. By adjusting different ratio of OCP to PLGA/PCL, three hybrid stents including PLGA/PCL, PLGA/PCL/2 wt%OCP, PLGA/PCL/4wt%OCP were successfully prepared. The PLGA/PCL/OCP membranes showed a decrease in fiber diameter compared with PLGA/PCL, leading to enhanced mechanical strength. In-vitro studies showed that PLGA/PCL/OCP membranes better supported cell adhesion, spreading and proliferation than PLGA/PCL. The incorporation of OCP via electrospinning also endowed the membranes with osteoinductive capacity, as evidenced by activation of ALP activity, increased gene expression of bone specific markers (such as Runx2, ALP, Col 1a1, OPN, OCN, BMP2), and mineral nodules formation compared to PLGA/PCL. Comparatively, PLGA/PCL/4wt%OCP showed better mechanical and biological performance than PLGA/PCL/2 wt%OCP, demonstrating the role of OCP in nanofiber membranes. Thus, the electrospun PLGA/PCL/OCP nanofiber membranes can be potentially developed as a promising hybrid stent for GBR.

Osteogenic Potential of Electrospun Poly(3-hydroxybutyrate-co-4-hydroxybutyrate)/ Poly(ethylene glycol) Nanofiber Membranes.

Nanofibers as niche-biomimetic scaffolds exhibit potential in bone tissue engineering (BTE). Here, poly(3-hydroxybutyrate-co-4-hydroxybutyrate) co-polymer (P34HB)/poly(ethylene glycol) (PEG) nanofiber membranes with a high hydrophilicity and mechanical properties were fabricated by introducing PEG to P34HB via electrospinning. The P34HB/PEG nanofibrous scaffolds were investigated for their potential in the osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells (BMSCs). By adjusting the ratio of PEG to P34HB, three scaffolds, including P34HB, P34HB/10 wt%PEG, and P34HB/30 wt%PEG, were successfully fabricated. The composite P34HB/PEG nanofiber membranes showed an enhanced hydrophilicity, a decreased fiber size, and an increased mechanical strength compared with those of P34HB. In-vitro studies showed that the P34HB/PEG membranes better supported cell adhesion, spreading, and proliferation than those of P34HB. The incorporation of PEG into the P34HB scaffold also promoted the osteoinduction capacity, as evidenced by activation of the alkaline phosphatase activity (ALP) activity, increased gene expression of bone specific markers (such as RUNX2, ALP, Col1a1, OPN, OCN, and BMP2), and mineral nodules formation. Comparatively, P34HB/10 wt%PEG showed a higher hydrophilicity and mechanical properties, as well as a better biological performance than the other membranes. Thus, the electrospun P34HB/PEG nanofiber membranes may be potentially developed as regenerative materials for BTE applications.