Multiplexed PLGA scaffolds with nitric oxide-releasing zinc oxide and melatonin-modulated extracellular vesicles for severe chronic kidney disease.

INTRODUCTION: With prevalence of chronic kidney disease (CKD) in worldwide, the strategies to recover renal function via tissue regeneration could provide alternatives to kidney replacement therapies. However, due to relatively low reproducibility of renal basal cells and limited bioactivities of implanted biomaterials along with the high probability of substance-inducible inflammation and immunogenicity, kidney tissue regeneration could be challenging. OBJECTIVES: To exclude various side effects from cell transplantations, in this study, we have induced extracellular vesicles (EVs) incorporated cell-free hybrid PMEZ scaffolds. METHODS: Hybrid PMEZ scaffolds incorporating essential bioactive components, such as ricinoleic acid grafted Mg(OH)2 (M), extracellular matrix (E), and alpha lipoic acid-conjugated ZnO (Z) based on biodegradable porous PLGA (P) platform was successfully manufactured. Consecutively, for functional improvements, melatonin-modulated extracellular vesicles (mEVs), derived from the human umbilical cord MSCs in chemically defined media without serum impurities, were also loaded onto PMEZ scaffolds to construct the multiplexed PMEZ/mEV scaffold. RESULTS: With functionalities of Mg(OH)2 and extracellular matrix-loaded PLGA scaffolds, the continuous nitric oxide-releasing property of modified ZnO and remarkably upregulated regenerative functionalities of mEVs showed significantly enhanced kidney regenerative activities. Based on these, the structural and functional restoration has been practically achieved in 5/6 nephrectomy mouse models that mimicked severe human CKD. CONCLUSION: Our study has proved the combinatory bioactivities of the biodegradable PLGA-based multiplexed scaffold for kidney tissue regeneration in 5/6 nephrectomy mouse representing a severe CKD model. The optimal microenvironments for the morphogenetic formations of renal tissues and functional restorations have successfully achieved the combinatory bioactivities of remarkable components for PMEZ/mEV, which could be a promising therapeutic alternative for CKD treatment.

Therapeutic potential of luteolin-loaded poly(lactic-co-glycolic acid)/modified magnesium hydroxide microsphere in functional thermosensitive hydrogel for treating neuropathic pain.

Neuropathic pain (NP) is a debilitating condition stemming from damage to the somatosensory system frequently caused by nerve injuries or lesions. While existing treatments are widely employed, they often lead to side effects and lack specificity. This study aimed to alleviate NP by developing an innovative sustained-release thermosensitive hydrogel system. The system incorporates hyaluronic acid (HA)/Pluronic F127 injectable hydrogel and bupivacaine (Bup, B) in combination with poly(lactic-co-glycolic acid; PLGA)/modified magnesium hydroxide (MH)/luteolin (Lut; PML) microspheres (PML@B/Gel). The PML@B/Gel was designed for localized and prolonged co-delivery of Bup and Lut as an anesthetic and anti-inflammatory agent, respectively. Our studies demonstrated that PML@B/Gel had exceptional biocompatibility, anti-inflammatory, and antioxidant properties. In addition, it exhibited efficient pain relief in in vitro cellular assays. Moreover, this functional hydrogel showed substantial sustained drug release while diminishing microglial activation. Consequently, it effectively mitigated mechanical allodynia and thermal hyperalgesia in in vivo rat models of chronic constriction injury (CCI). Based on our research findings, PML@B/Gel emerges as a promising therapeutic approach for the protracted treatment of NP.

Injectable Microparticle-containing hydrogel with controlled release of bioactive molecules for facial rejuvenation.

The skin is the largest organ and a crucial barrier for protection against various intrinsic and extrinsic factors. As we age, the skin's components become more vulnerable to damage, forming wrinkles. Among different procedures, hyaluronic acid-based hydrogel has been extensively utilized for skin regeneration and reducing wrinkles. However, it has limitations like low retention and weak mechanical properties. In this study, we suggested the poly(l-lactic acid) (PLLA) microparticles containing alkaline magnesium hydroxide and nitric oxide-generating zinc oxide and rejuvenative hyaluronic acid (HA) hydrogels including these functional microparticles and asiaticoside, creating a novel delivery system for skin rejuvenation and regeneration. The fabricated rejuvenative hydrogels have exhibited enhanced biocompatibility, pH neutralization, reactive oxygen species scavenging, collagen biosynthesis, and angiogenesis capabilities in vitro and in vivo. Additionally, an excellent volume retention ability was demonstrated due to the numerous hydrogen bonds that formed between hyaluronic acid and asiaticoside. Overall, our advanced injectable hydrogel containing functional microparticles, with controlled release of bioactive molecules, has a significant potential for enhancing the regeneration and rejuvenation of the skin.

Bulk Modification with Inorganic Particles and Immobilization of Extracellular Vesicles onto PDO Composite for Facial Rejuvenation.

BACKGROUND: The skin, a vital organ protecting against microorganisms and dehydration, undergoes structural decline with aging, leading to visible issues such as wrinkles and sagging. Reduced blood vessels exacerbate vulnerability, hindering optimal cellular function and compromising skin health. Polydioxanone (PDO) biomaterials address aging concerns but produce acidic byproducts, causing inflammation. Inorganic particles and nitric oxide (NO) play crucial roles in inhibiting inflammation and promoting skin regeneration. Stem cell-derived extracellular vesicles (EVs) contribute to intercellular communication, offering the potential to enhance cell functions. The study proposes a method to enhance PDO-based medical devices by incorporating inorganic particles and immobilizing EVs, focusing on facial rejuvenation, anti-inflammatory response, collagen formation, and angiogenesis. METHOD: PDO composites with inorganic particles such as magnesium hydroxide (MH) and zinc oxide (ZO) were prepared and followed by EV immobilization. Comprehensive characterization included biocompatibility, anti-inflammation, collagen formation ability, and angiogenesis ability. RESULTS: Bulk-modified PDO composites demonstrated even dispersion of inorganic particles, pH neutralization, and enhanced biocompatibility. EVs immobilized on the composite surface exhibited spherical morphology. Inflammation-related gene expressions decreased, emphasizing anti-inflammatory effects. Collagen-related gene and protein expressions increased, showcasing collagen formation ability. In addition, angiogenic capabilities were notably improved, indicating potential for skin rejuvenation. CONCLUSION: The study successfully developed and characterized PDO composites with inorganic particles and EVs, demonstrating promising attributes for medical applications. These composites exhibit biocompatibility, anti-inflammatory properties, collagen formation ability, and angiogenic potential, suggesting their utility in skin rejuvenation and tissue engineering. Further research and clinical validation are essential.

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.

Multifunctional PDO Thread Coated with Mg(OH)2/ZnO Nanoparticles and Asiaticoside for Improved Facial Lifting.

As interest in skin aesthetics increases, treatments to suppress aging are increasing. Among them, a facelift is the most effective procedure for improving wrinkles. However, side effects including inflammatory reactions occur due to the limitations of the PDO thread itself used during the procedure. In this paper, to improve the function of PDO thread, inorganic particles such as magnesium hydroxide (MH) and zinc oxide (ZO) and a biologically active agent, asiaticoside, were coated on the surface of PDO thread using ultrasonic coating technology. The coated thread exhibited excellent biocompatibility, promoted collagen synthesis, reduced inflammation, and stimulated angiogenesis in vitro and in vivo. The multifunctional PDO thread has shown promising potential for skin regeneration without inducing fibrosis. Such a practical coating system and the developed multifunctional PDO thread suggest new possibilities for developing safer and more effective materials in cosmetic and regenerative medicine to prevent aging and improve skin aesthetics.

Multi-modulation of immune-inflammatory response using bioactive molecule-integrated PLGA composite for spinal fusion.

Despite current developments in bone substitute technology for spinal fusion, there is a lack of adequate materials for bone regeneration in clinical applications. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is commercially available, but a severe inflammatory response is a known side effect. Bone graft substitutes that enhance osteogenesis without adverse effects are needed. We developed a bioactive molecule-laden PLGA composite with multi-modulation for bone fusion. This bioresorbable composite scaffold was considered for bone tissue engineering. Among the main components, magnesium hydroxide (MH) aids in reduction of acute inflammation affecting disruption of new bone formation. Decellularized bone extracellular matrix (bECM) and demineralized bone matrix (DBM) composites were used for osteoconductive and osteoinductive activities. A bioactive molecule, polydeoxyribonucleotide (PDRN, PN), derived from trout was used for angiogenesis during bone regeneration. A nano-emulsion method that included Span 80 was used to fabricate bioactive PLGA-MH-bECM/DBM-PDRN (PME2/PN) composite to obtain a highly effective and safe scaffold. The synergistic effect provided by PME2/PN improved not only osteogenic and angiogenic gene expression for bone fusion but also improved immunosuppression and polarization of macrophages that were important for bone tissue repair, using a rat model of posterolateral spinal fusion (PLF). It thus had sufficient biocompatibility and bioactivity for spinal fusion.

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.

Nitric Oxide-Releasing Bioinspired Scaffold for Exquisite Regeneration of Osteoporotic Bone via Regulation of Homeostasis.

Osteoporotic bone regeneration is a challenging process which involves the occurrence of sophisticated interactions. Although various polymeric scaffolds have been proposed for bone repair, research on osteoporotic bone regeneration remains practically limited. In particular, achieving satisfactory bone regeneration when using osteoporotic drugs is challenging including bisphosphonates. Here, a novel nitric oxide-releasing bioinspired scaffold with bioactive agents for the exquisite regeneration of osteoporotic bone is proposed. The bone-like biomimetic poly(lactic-co-glycolic acid) scaffold is first prepared in combination with organic/inorganic ECM and magnesium hydroxide as the base implant material. Nanoparticles containing bioactive agents of zinc oxide (ZO), alendronate, and BMP2 are incorporated to the biomimetic scaffold to impart multifunctionality such as anti-inflammation, angiogenesis, anti-osteoclastogenesis, and bone regeneration. Especially, nitric oxide (NO) generated from ZO stimulates the activity of cGMP and protein kinase G; in addition, ZO downregulates the RANKL/osteoprotegerin ratio by suppressing the Wnt/ß-catenin signaling pathway. The new bone is formed much better in the osteoporotic rat model than in the normal model through the regulation of bone homeostasis via the scaffold. These synergistic effects suggest that such a bioinspired scaffold could be a comprehensive way to regenerate exceptionally osteoporotic bones.

PLLA Composites Combined with Delivery System of Bioactive Agents for Anti-Inflammation and Re-Endothelialization.

The development of a biodegradable vascular scaffold (BVS) for the treatment of cardiovascular diseases (CVDs) still requires some improvement. Among them, re-endothelialization and anti-inflammation are clinically important to restore vascular function. In this study, we proposed a coating system to deliver hydrophilic bioactive agents to BVS using nanoemulsion and drop-casting methods. The poly(L-lactide) (PLLA) scaffold containing magnesium hydroxide (MH) was coated on the surface with bioactive molecules such as polydeoxyribonucleotide (PDRN), L-arginine (Arg, R), and mesenchymal stem cell-derived extracellular vesicles (EVs). PDRN upregulates the expression of VEGF as one of the A2A receptor agonists; and Arg, synthesized into nitric oxide by intracellular eNOS, induces endothelialization. In particular, EVs, which are composed of a lipid bilayer and transfer bioactive materials such as protein and nucleic acid, regulate homeostasis in blood vessels. Such a bioactive agent coating system and its PLLA composite suggest a new platform for the treatment of cardiovascular dysfunction.

Reduced restenosis and enhanced re-endothelialization of functional biodegradable vascular scaffolds by everolimus and magnesium hydroxide.

BACKGROUND: Coronary artery disease is a cardiovascular disease with a high mortality and mortality rate in modern society. Vascular stent insertion to restore blood flow is essential to treat this disease. A fully biodegradable vascular scaffold (BVS) is a vascular poly (L-lactic acid) (PLLA) stent that is receiving growing interest as this is biodegradable in the body and does not require secondary removal surgery. However, acidic byproducts composed of PLLA produced during the biodegradation of the BVS can induce an inflammatory response. Magnesium hydroxide, a basic inorganic particle, neutralizes the acidic byproducts of PLLA.  METHODS: In this study, we investigated using a BVS coated with everolimus and surface-modified magnesium hydroxide that suppresses smooth muscle cell proliferation and protects endothelial cells, respectively. The various characteristics of the functional stent were evaluated using in vitro and in vivo analyses.  RESULTS: The BVS was successfully prepared with evenly coated everolimus and surface-modified magnesium hydroxide. A neutral pH value was maintained by magnesium hydroxide during degradation, and everolimus was released for one month. The coated BVS effectively inhibited protein adsorption and platelet adhesion, demonstrating excellent blood compatibility. In vitro analysis showed that BVS protects endothelial cells with magnesium hydroxide and selectively inhibits smooth muscle cell proliferation via everolimus treatment. The functional BVS was inserted into porcine coronary arteries for 28 days, and the results demonstrated that the restenosis and inflammation greatly decreased and re-endothelialization was enhanced as compared to others. CONCLUSIONS: This study provides new insights into the design of drug-incorporated BVS stent for coronary artery disease.

Controlled vitamin D delivery with injectable hyaluronic acid-based hydrogel for restoration of tendinopathy.

Tendinopathy is a term used to describe tendon disorders that are marked by pain and a loss of function. Recent studies demonstrated that inflammation plays an important role throughout the broad spectrum of tendinopathy. Conventional treatments such as steroid injections, analgesics, and physical modalities simply give pain relief and do not alter the disease progression without the tendon regeneration effect. Tenocytes are responsible for maintaining the tendon matrix and understanding how they function is essential to studying new treatments for tendinopathy. Our previous study showed the protective effects of vitamin D (Vit D) on damaged tenocytes. Besides its well-known effects on bone metabolism, the non-classical action of Vit D is the pleiotropic effects on modulating immune function. In the present study, we developed a Vit D delivery system with hyaluronic acid (HA), which is one of the major components of the extracellular matrix that has anti-inflammation and wound-healing properties. A novel Vit D delivery system with cross-linked HA hydrogel (Gel) and Tween 80 (T80), Vit D@Gel/T80, could be a new regeneration technique for the treatment of tendinopathy. Vit D@Gel/T80 reduced TNF-α induced damage to human tenocytes in vitro. In an animal study, the Vit D@Gel/T80 injected group demonstrated tendon restoration features. As a result, this Vit D@Gel/T80 system might be a local injection material in the treatment for tendinopathy.

Enhanced Mechanical Properties and Anti-Inflammation of Poly(L-Lactic Acid) by Stereocomplexes of PLLA/PDLA and Surface-Modified Magnesium Hydroxide Nanoparticles.

Poly(L-lactic acid) (PLLA), as a biodegradable polymer, has attracted attention for use as a biomaterial. In order to apply PLLA as a cardiovascular stent, stronger mechanical properties and anti-inflammatory effects against acidic by-products are required. In this study, PLLA/PDLA stereocomplex microparticles (SC) were developed and surface-modified magnesium hydroxide (MH) nanoparticles with oligolactide were combined with these PLLA composites. The SC improved the mechanical properties of the PLLA composites through the formation of stereocomplex structures. The surface-modified MH nanoparticles showed enhanced mechanical properties due to the stereocomplex structures formed by PLLA chains and inhibited inflammatory responses by pH neutralization as a result of MH. Additionally, the MH nanoparticles containing PLLA composites had antibacterial effects and increased the viability of human vascular endothelial cells. This technology is expected to have great potential in the development of PLLA composite materials for the production of various medical devices, such as cardiovascular stents.

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.

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.

Poly(L-Lactic Acid) Composite with Surface-Modified Magnesium Hydroxide Nanoparticles by Biodegradable Oligomer for Augmented Mechanical and Biological Properties.

Poly(L-lactic acid) (PLLA) has attracted a great deal of attention for its use in biomedical materials such as biodegradable vascular scaffolds due to its high biocompatibility. However, its inherent brittleness and inflammatory responses by acidic by-products of PLLA limit its application in biomedical materials. Magnesium hydroxide (MH) has drawn attention as a potential additive since it has a neutralizing effect. Despite the advantages of MH, the MH can be easily agglomerated, resulting in poor dispersion in the polymer matrix. To overcome this problem, oligo-L-lactide-ε-caprolactone (OLCL) as a flexible character was grafted onto the surface of MH nanoparticles due to its acid-neutralizing effect and was added to the PLLA to obtain PLLA/MH composites. The pH neutralization effect of MH was maintained after surface modification. In an in vitro cell experiment, the PLLA/MH composites including OLCL-grafted MH exhibited lower platelet adhesion, cytotoxicity, and inflammatory responses better than those of the control group. Taken together, these results prove that PLLA/MH composites including OLCL-grafted MH show excellent augmented mechanical and biological properties. This technology can be applied to biomedical materials for vascular devices such as biodegradable vascular scaffolds.

Promotion of Bone Regeneration Using Bioinspired PLGA/MH/ECM Scaffold Combined with Bioactive PDRN.

Current approaches of biomaterials for the repair of critical-sized bone defects still require immense effort to overcome numerous obstacles. The biodegradable polymer-based scaffolds have been required to expand further function for bone tissue engineering. Poly(lactic-co-glycolic) acid (PLGA) is one of the most common biopolymers owing to its biodegradability for tissue regenerations. However, there are major clinical challenges that the byproducts of the PLGA cause an acidic environment of implanting site. The critical processes in bone repair are osteogenesis, angiogenesis, and inhibition of excessive osteoclastogenesis. In this study, the porous PLGA (P) scaffold was combined with magnesium hydroxide (MH, M) and bone-extracellular matrix (bECM, E) to improve anti-inflammatory ability and osteoconductivity. Additionally, the bioactive polydeoxyribonucleotide (PDRN, P) was additionally incorporated in the existing PME scaffold. The prepared PMEP scaffold has pro-osteogenic and pro-angiogenic effects and inhibition of osteoclast due to the PDRN, which interacts with the adenosine A2A receptor agonist that up-regulates expression of vascular endothelial growth factor (VEGF) and down-regulates inflammatory cytokines. The PMEP scaffold has superior biological properties for human bone-marrow mesenchymal stem cells (hBMSCs) adhesion, proliferation, and osteogenic differentiation in vitro. Moreover, the gene expressions related to osteogenesis and angiogenesis of hBMSCs increased and the inflammatory factors decreased on the PMEP scaffold. In conclusion, it provides a promising strategy and clinical potential candidate for bone tissue regeneration and repairing bone defects.

Prevention of chemotherapy-induced premature ovarian insufficiency in mice by scaffold-based local delivery of human embryonic stem cell-derived mesenchymal progenitor cells.

BACKGROUND: Premature ovarian insufficiency (POI) is one of the most serious side effects of chemotherapy in young cancer survivors. It may not only reduce fecundity but also affect lifelong health. There is no standard therapy for preserving ovarian health after chemotherapy. Recently, administration of embryonic stem cell-derived mesenchymal progenitor cells (ESC-MPCs) has been considered a new therapeutic option for preventing POI. However, the previous method of directly injecting cells into the veins of patients exhibits low efficacy and safety. This study aimed to develop safe and effective local delivery methods for the prevention of POI using two types of bioinspired scaffolds. METHODS: Female mice received intraperitoneal cisplatin for 10 days. On day 11, human ESC-MPCs were delivered through systemic administration using intravenous injection or local administration using intradermal injection and intradermal transplantation with a PLGA/MH sponge or hyaluronic acid (HA) gel (GEL) type of scaffold. PBS was injected intravenously as a negative control. Ovarian function and fertility were evaluated 4 weeks after transplantation. Follicle development was observed using hematoxylin and eosin staining. The plasma levels of sex hormones were measured using ELISA. Expression levels of anti-Müllerian hormone (AMH) and ki-67 were detected using immunostaining, and the quality of oocytes and embryos was evaluated after in vitro fertilization. The estrous cycles were observed at 2 months after transplantation. RESULTS: The local administration of human ESC-MPCs using the bioinspired scaffold to the backs of mice effectively prolonged the cell survival rate in vivo. The HA GEL group exhibited the best recovered ovarian functions, including a significantly increased number of ovarian reserves, estrogen levels, and AMH levels and decreased apoptotic levels. Furthermore, the HA GEL group showed improved quality of oocytes and embryos and estrous cycle regularity. CONCLUSIONS: HA GEL scaffolds can be used as new delivery platforms for ESC-MPC therapy, and this method may provide a novel option for the clinical treatment of chemotherapy-induced POI.

Multifunctional Biodegradable Vascular PLLA Scaffold with Improved X-ray Opacity, Anti-Inflammation, and Re-Endothelization.

Poly(L-lactic acid) (PLLA) has been used as a biodegradable vascular scaffold (BVS) material due to high mechanical property, biodegradability, and biocompatibility. However, acidic byproducts from hydrolysis of PLLA reduce the pH after the surrounding implanted area and cause inflammatory responses. As a result, severe inflammation, thrombosis, and in-stent restenosis can occur after implantation by using BVS. Additionally, polymers such as PLLA could not find on X-ray computed tomography (CT) because of low radiopacity. To this end, here, we fabricated PLLA films as the surface of BVS and divided PLLA films into two coating layers. At the first layer, PLLA film was coated by 2,3,5-triiodobenzoic acid (TIBA) and magnesium hydroxide (MH) with poly(D,L-lactic acid) (PDLLA) for radiopaque and neutralization of acidic environment, respectively. The second layer of coated PLLA films is composed of polydopamine (PDA) and then cystamine (Cys) for the generation of nitric oxide (NO) release, which is needed for suppression of smooth muscle cells (SMCs) and proliferation of endothelial cells (ECs). The characterization of the film surface was conducted via various analyses. Through the surface modification of PLLA films, they have multifunctional abilities to overcome problems of BVS effectively such as X-ray penetrability, inflammation, thrombosis, and neointimal hyperplasia. These results suggest that the modification of biodegradable PLLA using TIBA, MH, PDA, and Cys will have important potential in implant applications.