Osteoporotic Bone Regeneration via Plenished Biomimetic PLGA Scaffold with Sequential Release System.

Achieving satisfactory bone tissue regeneration in osteoporotic patients with ordinary biomaterials is challenging because of the decreased bone mineral density and aberrant bone microenvironment. In addressing this issue, a biomimetic scaffold (PMEH/SP), incorporating 4-hexylresorcinol (4HR), and substance P (SP) into the poly(lactic-go-glycolic acid) (PLGA) scaffold with magnesium hydroxide (M) and extracellular matrix (E) is introduced, enabling the consecutive release of bioactive agents. 4HR and SP induced the phosphorylation of p38 MAPK and ERK in human umbilical vein endothelial cells (HUVECs), thereby upregulating VEGF expression level. The migration and tube-forming ability of endothelial cells can be promoted by the scaffold, which accelerates the formation and maturation of the bone. Moreover, 4HR played a crucial role in the inhibition of osteoclastogenesis by interrupting the IκB/NF-κB signaling pathway and exhibiting SP, thereby enhancing the migration and angiogenesis of HUVECs. Based on such a synergistic effect, osteoporosis can be suppressed, and bone regeneration can be achieved by inhibiting the RANKL pathway in vitro and in vivo, which is a commonly known mechanism of bone physiology. Therefore, the study presents a promising approach for developing a multifunctional regenerative material for sophisticated osteoporotic bone regeneration.

Absorbable calcium and phosphorus bioactive membranes promote bone marrow mesenchymal stem cells osteogenic differentiation for bone regeneration.

Large segmental bone defects are commonly operated with autologous bone grafting, which has limited bone sources and poses additional surgical risks. In this study, we fabricated poly(lactide-co-glycolic acid) (PLGA)/ß-tricalcium phosphate (ß-TCP) composite membranes by electrostatic spinning and further promoted osteogenesis by regulating the release of ß-TCP in the hope of replacing autologous bone grafts in the clinical practice. The addition of ß-TCP improved the mechanical strength of PLGA by 2.55 times. Moreover, ß-TCP could accelerate the degradation of PLGA and neutralize the negative effects of acidification of the microenvironment caused by PLGA degradation. In vitro experiments revealed that PLGA/TCP10 membranes are biocompatible and the released ß-TCP can modulate the activity of osteoblasts by enhancing the calcium ions concentration in the damaged area and regulating the pH of the local microenvironment. Simultaneously, an increase in ß-TCP can moderate the lactate content of the local microenvironment, synergistically enhancing osteogenesis by promoting the tube-forming effect of human umbilical vein endothelial cells. Therefore, it is potential to utilize PLGA/TCP bioactive membranes to modulate the microenvironment at the site of bone defects to promote bone regeneration.

Injectable nanofiber-reinforced bone cement with controlled biodegradability for minimally-invasive bone regeneration.

Injectable materials show their special merits in regeneration of damaged/degenerated bones in minimally-invasive approach. Injectable calcium phosphate bone cement (CPC) has attracted broad attention for its bioactivity, as compared to non-degradable polymethyl methacrylate cement. However, its brittleness, poor anti-washout property and uncontrollable biodegradability are the main challenges to limit its further clinical application mainly because of its stone-like dense structure and fragile inorganic-salt weakness. Herein, we developed a kind of injectable CPC bone cement with porous structure and improved robustness by incorporating poly(lactide-co-glycolic acid) (PLGA) nanofiber into CPC, with carboxymethyl cellulose (CMC) to offer good injectability as well as anti-wash-out capacity. Furthermore, the introduction of PLGA and CMC also enabled a formation of initial porous structure in the cements, where PLGA nanofiber endowed the cement with a dynamically controllable biodegradability which provided room for cell movement and bone ingrowth. Interestingly, the reinforced biodegradable cement afforded a sustainable provision of Ca2+ bioactive components, together with its porous structure, to improve synergistically new bone formation and osteo-integration in vivo by using a rat model of femur condyle defect. Further study on regenerative mechanisms indicated that the good minimally-invasive bone regeneration may come from the synergistic enhanced osteogenic effect of calcium ion enrichment and the improved revascularization capacity contributed from the porosity as well as the lactic acid released from PLGA nanofiber. These results indicate the injectable bone cement with high strength, anti-washout property and controllable biodegradability is a promising candidate for bone regeneration in a minimally-invasive approach.

Size-Exclusive Nanoporous Biodegradable PLGA Capsules for Drug Delivery Implants and In Vivo Stability in the Posterior Segment.

The current standard of care for posterior segment eye diseases, such as neovascular age-related macular degeneration, diabetic macular edema, is frequent intravitreal injections or sustained-release drug implants. Intravitreal injections have a low incidence of serious complications such as retinal detachment, endophthalmitis, iatrogenic traumatic cataract, or iridocyclitis and injection-site reactions. However, there is a significant burden to the patient, the patient's family, and the health system because current intravitreal therapies require between every 4 and 12 week administration over many years. Drug implants have side effects due to the burst release of the drugs, and their release cannot be easily controlled after implantation. We have developed a size-exclusive nanoporous biodegradable PLGA capsule for dosage-controllable drug delivery implants. We have optimized the nanoporous structure by tuning the ratio between porogen and high molecular weight PLGA and tested the stability against passive leakage of the liposomal drug (1-2 µm) and the safety in vivo rabbit eyes for 6 months. Our results suggest that PLGA implants made of the nanoporous PLGA sheet can selectively release drug molecules, keeping the liposomal drug inside. In addition, the implant was biocompatible, causing no inflammation and foreign body response when implanted for 6 months. Overall, the implant shows great potential for on-demand dose-controllable drug release applications.

Biodegradable Microcarriers of Poly(Lactide-co-Glycolide) and Nano-Hydroxyapatite Decorated with IGF-1 via Polydopamine Coating for Enhancing Cell Proliferation and Osteogenic Differentiation.

In this study, insulin-like growth factor 1 (IGF-1) was successfully immobilized on the poly(lactide-co-glycolide)/hydroxyapatite (PLGA/HA) and pure PLGA microcarriers via polydopamine (pDA). The results demonstrated that the pDA layer facilitated simple and highly efficient immobilization of peptides on the microcarriers within 20 min. Mouse adipose-derived stem cells (ADSCs) attachment and proliferation on IGF-1-immobilized microcarriers were much higher than non-immobilized ones. More importantly, the IGF-1-immobilized PLGA/HA microcarriers significantly increased alkaline phosphatase (ALP) activity and expression of osteogenesis-related genes of ADSCs. Therefore, it is considered that the IGF-1-decorated PLGA/HA microcarriers will be of great value in the bone tissue engineering.

A PLGA-encapsulated chimeric protein protects against adherence and toxicity of enterotoxigenic Escherichia coli.

Enterotoxigenic Escherichia coli (ETEC) are the most common cause of diarrhea among children. Colonization factors and enterotoxins are the major ETEC candidate vaccines. Since protection against ETEC mostly occurs by induction of IgA antibodies, much effort is focused on the development of oral vaccines. In this study oral immunogenicity of a poly(lactic-co-glycolic acid) (PLGA) encapsulated chimeric protein containing CfaB, CstH, CotA and LTB (Heat-labile B subunit) was investigated. The protein was encapsulated in PLGA by double emulsion method and nanoparticles were characterized physicochemically. Immunogenicity was assessed by evaluating IgG1, IgG2 and IgA titers after BALB/c mice vaccination. Non aggregated nanoparticles had a spherical shape with an average particle size of 252.7±23 nm and 91.96±4.4% of encapsulation efficiency. Western blotting showed maintenance of the molecular weight and antigenicity of the released protein. Oral immunization of mice induced serum IgG and fecal IgA antibody responses. Immunization induced protection against ETEC binding to Caco-2 cells. The effect of LT toxin on fluid accumulation in ileal loops was neutralized by inhibition of enterotoxin binding to GM1-ganglosides. Delivery of the chimeric protein in PLGA elicited both systemic and mucosal immune responses. The findings could be exploited to development of oral multi-component ETEC prophylactic measures.