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Various methods based on gold nanoparticles (AuNPs) have been applied to enhance the photothermal effect. Among these methods, combining gold nanoparticles and stem cells has been suggested as a new technique for elevating the efficiency of photothermal therapy (PT) in terms of enhancing tumor targeting effect. However, to elicit the efficiency of PT using gold nanoparticles and stem cells, delivering large amounts of AuNPs into stem cells without loss should be considered.AuNPs, AuNPs-decorated silica nanoparticles, and silica-capped and AuNPs-decorated silica nanoparticles (SGSs) were synthesized and used to treat human mesenchymal stem cells (hMSCs). After evaluating physical properties of each nanoparticle, the concentration of each nanoparticle was estimated based on its cytotoxicity to hMSCs. The amount of AuNPs loss from each nanoparticle by exogenous physical stress was evaluated after exposing particles to a gentle shaking. After these experiments, in vitro and in vivo photothermal effects were then evaluated.SGS showed no cytotoxicity when it was used to treat hMSCs at concentration up to 20 μg/mL. After intravenous injection to tumor-bearing mice, SGS-laden hMSCs group showed significantly higher heat generation than other groups following laser irradiation. Furthermore, in vivo photothermal effect in the hMSC-SGS group was significantly enhanced than those in other groups in terms of tumor volume decrement and histological outcome.Our results suggest that additional silica layer in SGSs could protect AuNPs from physical stress induced AuNPs loss. The strategy applied in SGS may offer a prospective method to improve PT.

Control of the size and shape of nanoparticles significantly impacts the ability to control their physical and chemical properties. In this paper, we introduce a technique to split large nanoparticles into smaller ones. After the addition of ascorbic acid (AA), 50 nm-sized gold (Au) nanoparticles in the form of polycrystals were split into nanoparticles with sizes of 10 nm. We believe that AA plays a critical role in breaking down the Au particles. Additionally, this technique can be used to synthesize small AuPt bimetallic nanoparticles with a small amount of Pt on their surface showing that this reaction could help in the formation of a variety of small Au-based bimetallic nanoparticles.

Ice accumulation on vessels, airplanes, or on the off-shore plants surfaces causes major accidents and difficulties in operation. Therefore, highly efficient and environmentally friendly materials for use as deicing surfaces are in continuous demand. Accordingly, photothermal materials have gained enormous attention owing to their outstanding performance in the removal of ice. Herein, a gold nano-aggregate yolk-shell structure (GNA-YS) was introduced as a deicing material. GNA-YS was homogeneously dispersed in photocurable polyurethane acrylate and used to fabricate a highly efficient and sunlight-responsive GNA-YS film. Upon irradiation with an 810 nm light-emitting diode (LED) (135 mW cm−2), the temperature of the GNA-YS film increased by approximately 70 °C within 2 min, which rapidly (within 6 min) melted the accumulated ice. Moreover, the GNA-YS film exhibited a temperature increase of 15 °C in a refrigerator under LED illumination for 1 min. Additionally excellent stability was confirmed through repeated experiments. The newly developed deicing GNA-YS film has prospective applicability in vessels or airplanes.

The success of vascular progenitor cell transplantation to treat myocardial infarction (MI) is primarily limited by the low engraftment of delivered cells due to a washout effect during myocardium contraction. A clinically applicable biomaterial to improve cell retention is arguably needed to enable optimization of intramyocardial cell delivery. Here, we developed a novel therapeutic cell delivery method for MI treatment based on a photocrosslinkable gelatin methacryloyl (GelMA) hydrogel. A combination of human vascular progenitor cells (endothelial progenitors and mesenchymal stem cells) with the capacity to form functional vasculatures after transplantation, were injected with a rapid in-situ photopolymerization approach into the infarcted zone of mouse hearts. Our approach significantly improved acute cell retention and achieved a long-term beneficial post-MI cardiac healing, including stabilizing cardiac functions, preserving viable myocardium, and preventing cardiac fibrosis. Furthermore, the engrafted vascular cells polarized recruited bone marrow-derived neutrophils toward a non-inflammatory phenotype via TGFβ signaling, establishing a pro-regenerative microenvironment. Depletion of neutrophils canceled the therapeutic benefits produced by cell delivery in the ischemic hearts, indicating that the non-inflammatory, pro-regenerative neutrophils were indispensable mediators of cardiac remodeling. In summary, our novel GelMA hydrogel-based intramyocardial vascular cell delivery approach has the potential to improve the treatment of acute MI.

Transplantation of stem cell spheroids to ischemic tissues has been suggested as an effective method for treating ischemic disease, but its therapeutic efficacy varies according to the preparation methods for spheroids. We hypothesized that increasing cell compaction while preparing spheroids could improve the angiogenic efficacy of spheroids. Optimized human adipose derived stem cell (hADSC) spheroids were shown to upregulate cell adhesion molecule, and angiogenic paracrine factors expression with downregulated senescence and apoptotic markers expression. We noted that the low seeding density (1 × 104 cells (10KS)) had a far lower probability of forming spheroids than higher seeding densities (3 × 104 cells (30KS) and 1 × 105 cells (100KS)). The 30KS spheroids demonstrated higher cell density and expression levels of the angiogenic paracrine factor expression compared to those of 100 KS spheroids. 30KS spheroids with additional incubation (A30KS) showed significantly increased angiogenic paracrine factors and cell adhesion molecule expressions with decreased senescence expression compared to those in 30KS spheroids. Transplanting A30KS spheroids showed significantly enhanced therapeutic angiogenesis in mouse hindlimb ischemia model compared to conventional spheroid transplantation. This study successfully defined a set of novel criteria for spheroid culture, which may contribute to future stem cell therapies.

This study investigated a selective and sensitive theragnosis system for the specific targeting of the membrane and nuclei based on visible-light and pH-responsive TiO2-integrated cross-linked carbon dot (C-CD/TiO2) for tumor detection and controllable photothermal therapy. The cross-linking system was formed by boronate ester linkages between the TiO2-immobilized Dopa-decyl (D-CD) and zwitterionic-formed CD (Z-CD) for nuclear targeting, which showed fluorescence "off" at physiological pH. The fluorescence recovered to the "on" state in acidic cancer cells owing to cleavages of the boronate ester bonds, resulting in the disruption of the Forster resonance energy transfer that generated different CDs useful for tumor-selective biosensors and therapy. D-CD, which is hydrophobic, can penetrate the hydrophobic sites of the cell membrane; it caused a loss in the hydrophobicity of these sites after visible-light irradiation. This was achieved by the photocatalytic activity of the TiO2 modulating energy bandgap, whereas the Z-CD targeted the nucleus, as confirmed by merged confocal microscopy images. D-CD augmented by photothermal heat also exhibited selective anticancer activity in the acidic tumor condition but showed only minimal effects at a normal site at pH 7.4. After C-CD/TiO2 injection to an in vivo tumor model, C-CD/TiO2 efficiently ablated tumors under NIR light irradiation. The C-CD/TiO2 group showed up-regulation of the pro-apoptotic markers such as P53 and BAX in tumor. This material exhibited its potential as a theragnostic sensor with excellent biocompatibility, high sensitivity, selective imaging, and direct anticancer activity via photothermal therapy.

Light‐based therapy such as photobiomodulation (PBM) reportedly produces beneficial physiological effects in cells and tissues. However, most reports have focused on the immediate and instant effects of light. Considering the physiological effects of natural light exposure in living organisms, the latent reaction period after irradiation should be deliberated. In contrast to previous reports, we examined the latent reaction period after light exposure with optimized irradiating parameters and validated novel therapeutic molecular mechanisms for the first time. we demonstrated an organic light‐emitting diode (OLED)‐based PBM (OPBM) strategy that enhances the angiogenic efficacy of human adipose‐derived stem cells (hADSCs) via direct irradiation with red OLEDs of optimized wavelength, voltage, current, luminance, and duration, and investigated the underlying molecular mechanisms. Our results revealed that the angiogenic paracrine effect, viability, and adhesion of hADSCs were significantly intensified by our OPBM strategy. Following OPBM treatment, significant changes were observed in HIF‐1α expression, intracellular reactive oxygen species levels, activation of the receptor tyrosine kinase, and glycolytic pathways in hADSCs. In addition, transplantation of OLED‐irradiated hADSCs resulted in significantly enhanced limb salvage ratio in a mouse model of hindlimb ischemia. Our OPBM might serve as a new paradigm for stem cell culture systems to develop cell‐based therapies in the future.

Mesenchymal stem cells such as human adipose tissue-derived stem cells (hADSCs) have been used as a representative therapeutic agent for tissue regeneration because of their high proliferation and paracrine factor-secreting abilities. However, certain points regarding conventional ADSC delivery systems, such as low cell density, secreted cytokine levels, and cell viability, still need to be addressed for treating severe wounds. In this study, we developed a three-dimensional (3D) cavity-structured stem cell-laden system for overdense delivery of cells into severe wound sites. Our system includes a hydrophobic surface and cavities that can enhance the efficiency of cell delivery to the wound site. In particular, the cavities in the system facilitate hADSC spheroid formation, increasing therapeutic growth factor expression compared with 2D cultured cells. Our hADSC spheroid-loaded patch exhibited remarkably improved cell localization at the wound site and dramatic therapeutic efficacy compared to the conventional cell injection method. Taken together, the hADSC spheroid delivery system focused on cell delivery, and stem cell homing effect at the wound site showed a significantly enhanced wound healing effect. By overcoming the limitations of conventional cell delivery methods, our overdense cell delivery system can contribute to biomedical and clinical applications.

Low-level light therapy (LLLT) is a safe and noninvasive technique that has drawn attention as a new therapeutic method to treat various diseases. However, little is known so far about the effect of blue light for LLLT due to the generation of reactive oxygen species (ROS) that can cause cell damage. We introduced a blue organic light-emitting diode (bOLED) as a safe and effective light source that could generate a low amount of heat and luminance compared to conventional light sources (e.g., light-emitting diodes). We compared phototoxicity of bOLED light with different light fluences to human adipose-derived stem cells (hADSC). We further explored molecular mechanisms involved in the therapeutic efficacy of bOLED for enhancing angiogenic properties of hADSC, including intracellular ROS control in hADSCs. Using optimum conditions of bOLED light proposed in this study, photobiomodulation and angiogenic properties of hADSCs were enhanced. These findings might open new methods for using blue light in LLLT. Such methods can be implemented in future treatments for ischemic disease.

In this study we developed a dual therapeutic metal ion-releasing nanoparticle for advanced osteogenic differentiation of stem cells. In order to enhance the osteogenic differentiation of human mesenchymal stem cells (hMSCs) and induce angiogenesis, zinc (Zn) and iron (Fe) were synthesized together into a nanoparticle with a pH-sensitive degradation property. Zn and Fe were loaded within the nanoparticles to promote early osteogenic gene expression and to induce angiogenic paracrine factor secretion for hMSCs. In vitro studies revealed that treating an optimized concentration of our zinc-based iron oxide nanoparticles to hMSCs delivered Zn and Fe ion in a controlled release manner and supported osteogenic gene expression (RUNX2 and alkaline phosphatase) with improved vascular endothelial growth factor secretion. Simultaneous intracellular release of Zn and Fe ions through the endocytosis of the nanoparticles further modulated the mild reactive oxygen species generation level in hMSCs without cytotoxicity and thus improved the osteogenic capacity of the stem cells. Current results suggest that our dual ion releasing nanoparticles might provide a promising platform for future biomedical applications.

Cell therapy based on human adipose derived stem cells (hADSCs) is a known potential therapeutic approach to induce angiogenesis in ischemic diseases. However, the therapeutic efficacy of direct hADSC injection is limited by a low cell viability and poor cell engraftment after administration. To improve the outcomes of this kind of approach, various types of nanoparticles have been utilized to improve the therapeutic efficacy of hADSC transplantation. Despite their advantages, the adverse effects of nanoparticles, such as genetic damage and potential oncogenesis based on non-degradable property of nanoparticles prohibit the application of nanoparticles toward the clinical applications. Herein, we designed a transition metal based inorganic nanocluster able of pH-selective degradation (ps-TNC), with the aim of enhancing an hADSC based treatment of mouse hindlimb ischemia. Our ps-TNC was designed to undergo degradation at low pH conditions, thus releasing metal ions only after endocytosis, in the endosome. To eliminate the limitations of both conventional hADSC injection and non-degradable property of nanoparticles, we have collected conditioned medium (CM) from the ps-TNC treated hADSCs and administrated it to the ischemic lesions. We found that intracellular increment of transition metal ion upregulated the hypoxia-inducible factor 1α, which can induce vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expressions. Based on the molecular mechanism, the secretion of VEGF and bFGF by ps-TNC treated hADSCs showed a significant improvement compared to that of untreated cells. Injecting the CM collected from ps-TNC treated hADSCs into the mouse hindlimb ischemia model (ps-TNC-CM group) showed significantly improved angiogenesis in the lesions, with improved limb salvage and decreased muscle degeneration compared to the group injected with CM collected from normal hADSCs (CM group). This study suggests a novel strategy, combining a known angiogenesis molecular mechanism with both an improvement on conventional stem cell therapy and the circumvention of some limitations still present in modern approaches based on nanoparticles.

This study investigated a selective and sensitive theragnosis system for the specific targeting of the membrane and nuclei based on visible-light and pH-responsive TiO

Inorganic nanomaterials or nanoparticles (INPs) have drawn high attention for their usage in the biomedical field. In addition to the facile synthetic and modifiable property of INPs, INPs have various unique properties that originate from the components of the INPs, such as metal ions that are essential for the human body. Apart from their roles as components of the human body, inorganic materials have unique properties, such as magnetic, antibacterial, and piezoelectric, so that INPs have been widely used as either carriers or inducers. However, most of the bio-applicable INPs, especially those consisting of metal, can cause cytotoxicity. Therefore, INPs require modification to alleviate the harmful effect toward the cells by controlling the release of metal ions from INPs. Even though many attempts have been made to modify INPs, many things, including the side effects of INPs, still remain as obstacles in the bio-application, which need to be elucidated. In this chapter, we introduce novel INPs in terms of their synthetic method and bio-application in tissue engineering.

Here, we report that Fe ions delivered into human mesenchymal stem cells (hMSCs) by bioreducible metal nanoparticles (NPs) enhance their angiogenic and cell-homing efficacy by controlling ion-triggered intracellular reactive oxygen species (ROS) and improve cell migration, while reducing cytotoxicity. Endosome-triggered iron-ion-releasing nanoparticles (ETIN) were designed to be low-pH responsive to take advantage of the low-pH conditions (4-5) of endosomes for in situ iron-ion release. Due to the different redox potentials of Fe and Au, only Fe could be ionized and released from our novel ETIN, while Au remained intact after ETIN endocytosis. Treatment with an optimal amount of ETIN led to a mild increase in intracellular ROS levels in hMSCs, which enhanced the expression of HIF-1α, a key trigger for angiogenic growth factor secretion from hMSCs. Treatmetn of hMSCs with ETIN significantly enhanced the expression of angiogenesis- and lesion-targeting-related genes and proteins. Transplantation of ETIN-treated hMSCs significantly enhanced angiogenesis and tissue regeneration in a wound-closing mouse model compared with those in untreated mice and mice that underwent conventional hMSC transplantation.

Additional file 1: Additional experiment.

This review article summarizes the recent research trends for the treatment of type 1 diabetes (T1D) based on islets transplantation and drug delivery system. The research concerns ongoing development and future suggestions in T1D treatment with their limitations. T1D is one of the representative chronic disease causing human death with hypoglycemia and ketoacidosis. As the T1D incidence rate and market size increase, the need for T1D treatment is growing worldwide. Islets transplantation and drug delivery system with or without insulin have shown the potentials for effective T1D treatment. This review discusses various recent methods for islets transplantation derived from human stem cells or animal tissue. In addition to cell transplantation methods, islet transplantation with other cells or biomaterials that can deliver insulin or non-insulin drugs simultaneously are discussed. There are several limitations in the use of conventional islet and drug delivery system based on insulin and non-insulin for T1D treatment. This manuscript reviews the recent research results based on limelight research subjects about T1D treatment and their limitations.

Metal and oxide nanoparticles (NPs) are attracting extensive attention in biomedical applications, including bioimaging and drug delivery. However, it is difficult to use these NPs as therapeutic agents for specific cell and tissue treatments because of limitations such as material oxidization and cell toxicity. Herein, we synthesized Cu-based angiogenic metal nanoparticles (Cu-AMNs), using a galvanic replacement reaction of Cu NPs and Au precursor, which stabilized and upregulated intracellular behaviors in human adipose-derived stem cells (hADSCs). Our novel therapeutic Cu-AMNs showed remarkable advantages in cell treatment, such as low mitochondrial damage, reduced ATP consumption, decreased cytotoxicity, mild reactive oxygen species generation with enhanced angiogenic paracrine factor secretion, and improved hypoxia inducible factor-1 alpha (HIF-1α) expression. Through the improved expression of HIF-1α, vascular endothelial growth factor (VEGF) secretion was prolonged for 3 days, even in re-attached hADSCs. In addition, Cu-AMNs improved other angiogenic factors and the amount of exocytosed Cu from hADSCs, resulting in strong development of tubular formation by human umbilical vein endothelial cells in vitro. Finally, transplantation of Cu-AMN-treated hADSCs in mice led to a significant in vivo increase in angiogenesis and blood perfusion in a mouse hindlimb ischemia model compared with conventional hADSC therapy.

Low cell engraftment is a major problem in tissue engineering. Although various methods related with cell sheets have been attempted to resolve the issue, low cell viability due to oxygen and nutrient depletion remains an obstacle toward advanced therapeutic applications. Cell therapy using fibroblasts is thought of as a good alternative due to the short doubling times of fibroblasts together with their immunomodulatory properties. Furthermore, three-dimensional (3D) fibroblasts exhibit unique angiogenic and inflammation-manipulating properties that are not present in two-dimensional (2D) forms. However, the therapeutic effect of 3D fibroblasts in tissue regeneration has not been fully elucidated. Macrophage polarization has been widely studied, as it stimulates the transition from the inflammation to the proliferation phase of wound healing. Although numerous strategies have been developed to achieve better polarization of macrophages, the low efficacy of these strategies and safety issues remain problematic. To this end, we introduced a biocompatible flat patch with specifically designed holes that form a spheroids-incorporated human dermal fibroblast sheet (SIS) to mediate the activity of inflammatory cytokines for M2 polarization and increase angiogenic efficacy. We further confirmed in vivo enhancement of wound healing with an SIS-laden skin patch (SISS) compared to conventional cell therapy.

Injecting human mesenchymal stem cells (hMSCs) at wound sites is known to have a therapeutic effect, however, hMSCs have several limitations, such as low viability and poor engraftment after injection, as well as a potential risk of oncogenesis. The use of a conditioned medium (CM) was suggested as an alternative method for treating various wounds instead of direct hMSC administration. In addition to not having the adverse effects associated with hMSCs, a CM can be easily mass produced and can be stored for long-term, thereby making it useful for clinical applications. In general, a CM is collected from hMSCs with low passage number, whereas, the hMSCs with high passage number are usually discarded because of their low therapeutic efficacy as a result of reduced angiogenic factor secretion. Herein, we used a CM collected from high passage number (passage 12, P12) hMSCs treated with gold-iron nanoparticles (AuFe NPs). Our AuFe NPs were designed to release the iron ion intracellularly via endocytosis. Endosomes with low pH can dissolve iron from AuFe NPs, and thus, the intracellularly released iron ions up-regulate the hypoxia-inducible factor 1&alpha, and vascular endothelial growth factor (VEGF) expression. Through this mechanism, AuFe NPs improve the amount of VEGF expression from P12 hMSCs so that it is comparable to the amount of VEGF expression from low passage number (passage 6, P6), without treatment. Furthermore, we injected the CM retrieved from P12 MSCs treated with AuFe NPs in the mouse skin wound model (AuFe P12 group). AuFe P12 group revealed significantly enhanced angiogenesis in the mouse skin wound model compared to the high passage hMSC CM-injected group. Moreover, the result from the AuFe P12 group was similar to that of the low passage hMSC CM-injected group. Both the AuFe P12 group and low passage hMSC CM-injected group presented significantly enhanced re-epithelization, angiogenesis, and tissue remodeling compared to the high passage hMSC CM-injected group. This study reveals a new strategy for tissue regeneration based on CM injection without considering the high cell passage count.

Keratinocytes are frequently used for the biological and biomedical remodeling of damaged skin tissues. However, low cell viability, poor cell maintenance, and lack of paracrine factors hamper the therapeutic efficacy of keratinocytes for skin wound healing. Here, we report the fabrication of a 2D and 3D co-spatial compartmentalized patch (CSCP) for a microscale keratinocyte-engineering platform and a novel method for delivering keratinocytes to enhance wound closure compared to that achieved by the conventional keratinocyte delivery method. Micro-sized cylinders engraved within a polydimethylsiloxane (PDMS) substrate were fabricated to induce and trap 3D keratinocyte clusters. Simultaneously, the outer surface of the PDMS substrate was used as an area for 2D keratinocyte culture. As a result, the CSCPs could be simultaneously applied for both 2D and 3D in vitro keratinocyte culture and in vivo cell delivery. The 3D keratinocytes increased the cell density for delivery and angiogenic factor expression but decreased the cell proliferation, which was complemented by the high proliferation of 2D keratinocytes. Our in vivo results confirmed that the therapeutic efficacy of keratinocytes for wound closure was significantly enhanced when the cells were delivered in a 2D and 3D co-spatial manner. We used the CSCPs to improve the wound closing efficacy of keratinocytes by simple dual spatial control, which was supported by the simultaneous upregulation of molecular mechanisms, and provided new insights for the development of a large-scale keratinocyte delivery system for skin wound healing.

Electrical stimulation (ES) is known to affect the wound healing process by modulating skin cell behaviors. However, the conventional clinical devices that can generate ES for promoting wound healing require patient hospitalization due to large-scale of the extracorporeal devices. Herein, we introduce a disposable photovoltaic patch that can be applied to skin wound sites to control cellular microenvironment for promoting wound healing by generating ES. In vitro experiment results show that exogenous ES could enhance cell migration, proliferation, expression of extracellular matrix proteins, and myoblast differentiation of fibroblasts which are critical for wound healing. Our disposable photovoltaic patches were attached to the back of skin wound induced mice. Our patch successfully provided ES, generated by photovoltaic energy harvested from the organic solar cell under visible light illumination. In vivo experiment results show that the patch promoted cutaneous wound healing via enhanced host-inductive cell proliferation, cytokine secretion, and protein synthesis which is critical for wound healing process. Unlike the current treatments for wound healing that engage passive healing processes and often are unsuccessful, our wearable photovoltaic patch can stimulate regenerative activities of endogenous cells and actively contribute to the wound healing processes.