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.

Endogenous stimulus-responsive nitric oxide releasing bioactive liposome for a multilayered drug-eluting balloon.

Drug-eluting balloon (DEB) system has been widely utilized for percutaneous coronary intervention (PCI), treating atherosclerosis to overcome the limitations of cardiovascular stents. With the anti-proliferative drug, everolimus (EVL), nitric oxide (NO) plays a key bioregulator role to facilitate the angiogenesis of endothelial cells (ECs) and inhibit the cell proliferation of smooth muscle cells (SMCs) in the lesions of cardiovascular diseases. Due to the very short lifetime and limited exposure area of NO in the body, the continuous release and efficient delivery of NO must be carefully considered. In this respect, a liposome-containing disulfide bonding group was introduced as a delivery vehicle of EVL and NO with the continuous release of NO via successive reaction cycles with GSH and SNAP in the blood vessel without the need for exogenous stimulations. With a multilayer coating platform consisting of a polyvinylpyrrolidone (PVP)/EVL-laden liposome with NO (EVL-NO-Lipo)/PVP, we precluded the loss of the EVL-encapsulated liposome with NO release during the transition time and maximized the transfer rate from the surface of DEB to the tissues. The sustained release of NO was monitored using a nitric oxide analyzer (NOA), and the synergistic bioactivities of EVL and NO were proved in EC and SMC with angiogenesis and cell proliferation-related assays. From the results of hemocompatibility and ex vivo studies, the feasibility was provided for future in vivo applications of the multilayer-coated DEB system.

Bioactive PCL microspheres with enhanced biocompatibility and collagen production for functional hyaluronic acid dermal fillers.

Polymeric microspheres containing magnesium hydroxide (MH) and a bioactive agent (BA), such as apocynin (APO) and astaxanthin (ATX), have been prepared as functional dermal fillers with enhanced physicochemical and biological performance. In this study, polycaprolactone (PCL)-based microspheres were produced with a uniform size of about 30-40 µm by utilizing a membrane emulsification device. MH from the PCL/MH microspheres effectively neutralized acidic products from PCL degradation. For in vitro cell experiments, when acidic degradation products (6-hydroxycaproic acid, HCA) were treated with MH, the acidic pH was neutralized to induce wound healing and suppress inflammation. The microspheres comprised of BA had a sustained release of the BA, without an initial burst release. Remarkably, the ATX added into the microspheres was maintained for 16 weeks and displayed positive attributes, such as tissue regeneration and collagen production improvement, as noted by in vivo testing. Overall, these results suggest that the bioactive PCL microspheres containing ATX have excellent potential as a functional dermal filler for skin aesthetics and facial plastic surgery.

Fat Graft with Allograft Adipose Matrix and Magnesium Hydroxide-Incorporated PLGA Microspheres for Effective Soft Tissue Reconstruction.

BACKGROUND: Autologous fat grafting is one of the most common procedures used in plastic surgery to correct soft tissue deficiency or depression deformity. However, its clinical outcomes are often suboptimal, and lack of metabolic and architectural support at recipient sites affect fat survival leading to complications such as cyst formation, calcification. Extracellular matrix-based scaffolds, such as allograft adipose matrix (AAM) and poly(lactic-co-glycolic) acid (PLGA), have shown exceptional clinical promise as regenerative scaffolds. Magnesium hydroxide (MH), an alkaline ceramic, has attracted attention as a potential additive to improve biocompatibility. We attempted to combine fat graft with regenerative scaffolds and analyzed the changes and viability of injected fat graft in relation to the effects of injectable natural, and synthetic (PLGA/MH microsphere) biomaterials. METHODS: In vitro cell cytotoxicity, angiogenesis of the scaffolds, and wound healing were evaluated using human dermal fibroblast cells. Subcutaneous soft-tissue integration of harvested fat tissue was investigated in vivo in nude mouse with random fat transfer protocol Fat integrity and angiogenesis were identified by qRT-PCR and immunohistochemistry. RESULTS: In vitro cell cytotoxicity was not observed both in AAM and PLGA/MH with human dermal fibroblast. PLGA/MH and AAM showed excellent wound healing effect. In vivo, the AAM and PLGA/MH retained volume compared to that in the only fat group. And the PLGA/MH showed the highest angiogenesis and anti-inflammation. CONCLUSION: In this study, a comparison of the volume retention effect and angiogenic ability between autologous fat grafting, injectable natural, and synthetic biomaterials will provide a reasonable basis for fat grafting.

The antagonistic effect of magnesium hydroxide particles on vascular endothelial activation induced by acidic PLGA degradation products.

Although drug-eluting stents (DESs) are mainly coated with biodegradable polymers such as PLGA and PLLA, their acidic degradation products can alter the local microenvironment and affect the homeostasis of adjacent tissue. Previously, we developed anti-inflammatory PLGA-based materials including magnesium hydroxide (MH) to relieve the side effects caused by PLGA degradation. However, the underlying molecular mechanism of its protective effects has not yet been clarified. Here, we demonstrated the pathological mechanism of vascular endothelial activation caused by PLGA by-products. The PLGA by-products accumulated in HCAECs through MCT1, followed by oxidative stress and the activation of the MAPK/NF-κB signaling pathway. Finally, the PLGA by-products increased the expression of VCAM-1 as well as the secretion of proinflammatory cytokines. However, the addition of MH particles significantly diminished the activation of this molecular pathway and the expression of inflammation-related factors induced by acidic PLGA degradation products. Furthermore, Mg2+ released from MH particles restored endothelial function in both intracellular and extracellular spaces. Taken together, MH particles prevent the accumulation of PLGA degradation products in HCAECs, thereby repressing the associated vascular endothelial activation. These findings on the biochemical mechanisms are expected to provide important clues for addressing the safety issues in nearly all biodegradable polymer-based implants.

Enhanced mechanical and biological characteristics of PLLA composites through surface grafting of oligolactide on magnesium hydroxide nanoparticles.

Poly(l-lactic acid) (PLLA) is a biocompatible and biodegradable polymer that has received much attention as a biomedical material. However, PLLA also produces by-products that acidify the surrounding tissues during in vivo degradation, which induces inflammatory responses. To overcome these problems, magnesium hydroxide nanoparticles (nano-magnesium hydroxide; nMH) were added to the PLLA matrix as a bioactive filler that can suppress inflammatory responses by neutralizing the acidified environment caused by the degradation of PLLA. Despite the advantages of nMH, the strong cohesion of these nanoparticles toward each other makes it difficult to manufacture a polymer matrix containing homogeneous nanoparticles through thermal processing. Here, we prepared two types of surface-modified nMH with oligolactide (ODLLA) utilizing grafting to (GT) and grafting from (GF) strategies to improve the mechanical and biological characteristics of the organic-inorganic hybrid composite. The incorporation of surface-modified nMH not only enhanced mechanical properties, such as Young's modulus, but also improved homogeneity of magnesium hydroxide particles in the PLLA matrix due to the increase in interfacial interaction. Additionally, the PLLA composites with surface-modified nMH exhibited reduced bulk erosion during hydrolytic degradation with lower cytotoxicity and immunogenicity. Hemocompatibility tests on the PLLA composites with nMH showed a higher albumin to fibrinogen ratio (AFR) and a lower influence of platelet activation, when compared with unmodified control samples. Taken all together, the surface-modified nMH could be seen to successfully improve the physical and biological characteristics of polymer composites. We believe this technology has great potential for the development of hybrid nanocomposites for biomedical devices, including cardiovascular implants.

Hydrophilic surface modification of poly(methyl methacrylate)-based ocular prostheses using poly(ethylene glycol) grafting.

Ocular prostheses are custom-made polymeric inserts that can be placed in anophthalmic sockets for cosmetic rehabilitation. Prosthetic eye wearers have reduced tear amount, and they often experience dry eye symptoms including dryness, irritation, discomfort, and discharge. Most modern ocular prostheses are made of poly(methyl methacrylate) (PMMA), which is highly hydrophobic. Previous research has shown that improving the wettability of contact lens materials decreases its wearers discomfort by increasing lubrication. Therefore, hydrophilic modification of PMMA-based ocular prostheses might also improve patient discomfort by improving lubrication. We modified the surfaces of PMMA-based ocular prostheses using poly(ethylene glycol) (PEG), which is hydrophilic. To do this, we used two strategies. One was a "grafting from" method, whereby PEG was polymerized from the PMMA surface. The other was a "grafting to" method, which involved PEG being covalently bonded to an amine-functionalized PMMA surface. Assessments involving the water contact angle, ellipsometry, and X-ray photoelectron spectroscopy indicated that PEG was successfully introduced to the PMMA surfaces using both strategies. Scanning electron microscopy and atomic force microscopy images revealed that neither strategy caused clinically significant alterations in the PMMA surface morphology. In vitro bacterial adhesion assessments showed that the hydrophilic modifications effectively reduced bacterial adhesion without inducing cytotoxicity. These results imply that hydrophilic surface modifications of conventional ocular prostheses may decrease patient discomfort and ocular prosthesis-related infections.