Pore Structure and Deformation Correlation of an Aluminum Foam Sandwich Subject to Three-Point Bending.

An Al-Si matrix foam sandwich (AFS) with 6063 Al alloy cover sheets was fabricated by hot rolling combined with melt foaming. A foamable AlSiMg1/SiCp matrix precursor was prepared by the melting route. Hot rolling at 480 °C was carried out to obtain a mechanical bonding interface between the cover sheet and the foamable precursor. Meanwhile, the pore structure of the AFS was deeply affected by the foaming temperature and foaming time during the foaming process. Different pore growth mechanics of the crack-like pore disappearance mechanism (CDM) and pore active expansion mechanism (AEM) were concluded based on the pressure difference in pores inside and outside. Three bending tests were applied to three types of AFSs with different pore structures to evaluate the relation between pore structures and AFS mechanical properties. The bending property of the AFS with fewer layers of pores is like that of a dense material. The bending property of the AFS with a pore size in the range of 0~1 mm presents a typical sandwich shear failure mode. The AFS with a uniform pore structure, in which the shapes of the pores are predominately polygons and the pore diameter is concentrated in the range of 0.5~3 mm, processes a good energy absorption capacity, and the bending stress-strain curve fluctuates greatly after the first stress drop.

Tumor-Specific Photothermal-Therapy-Assisted Immunomodulation via Multiresponsive Adjuvant Nanoparticles.

Multiresponsive adjuvant nanoparticles (RMmAGL) are fabricated to perform tumor-specific photothermal therapy while regulating the behavior of tumor-associated immune cells for primary tumor eradication and metastasis inhibition. Core-satellite-like RMmAGL have a core of mannose-functionalized mesoporous silica nanoparticles loaded with the TLR7 agonist imiquimod (R837@MSN-mannose) connected via hydrazone bonds to satellites of glutamine (Glu)- and lysine (Lys)-comodified gold nanoparticles (AuNPs-Glu/Lys). During therapy, the acidic environment in tumor tissue cleaves the hydrazone bonds to release AuNPs-Glu/Lys, which further accumulate in tumor cells. After internalization, photothermal agents (aggregated AuNPs-Glu/Lys) are generated in situ through the intratumoral enzyme-catalyzed reaction between Glu and Lys, resulting in tumor-specific photothermal therapy. The detachment of AuNPs-Glu/Lys also triggers the release of R837, which matured dendritic cells (DCs) via a vaccine-like mechanism along with the tumor-associated antigens generated by photothermal therapy. These matured DCs further activates surrounding T cells for immunotherapy. Moreover, the resulting free MSN-mannose serves as an artificial glycocalyx to continuously induce the polarization of tumor-associated macrophages from an immunosuppressive phenotype to an inflammatory phenotype, thus further enhancing immunotherapy. Both in vivo and in vitro experiments demonstrate significant inhibition of malignant tumors after therapy.

Manipulation and elimination of circulating tumor cells using multi-responsive nanosheet for malignant tumor therapy.

Tumor recurrence caused by metastasis is a major cause of death for patients. Thus, a strategy to manipulate the circulating tumor cells (CTCs, initiators of tumor metastasis ) and eliminate them along with the primary tumor has significant clinical significance for malignant tumor therapy. In this study, a magnet-NIR-pH multi-responsive nanosheet (Fe3O4@SiO2-GO-PEG-FA/AMP-DOX, FGPFAD) was fabricated to capture CTCs in circulation, then magnetically transport them to the primary tumor, and finally perform NIR-dependent photothermal therapy as well as acidic-environment-triggered chemotherapy to destroy both the CTCs and the primary tumor. The FGPFAD nanosheet consists of silica-coated ferroferric oxide nanoparticles (Fe3O4@SiO2, magnetic targeting agent), graphene oxide (GO, photothermal therapy agent), polyethylene glycol (PEG, antifouling agent for sustained circulation), folic acid (FA, capturer of CTCs) and antimicrobial-peptide-conjugated doxorubicin (AMP-DOX, agent for chemotherapy), in which the AMP-DOX was bound to the FGPFAD nanosheet via a cleavable Schiff base to achieve acidic-environment-triggered drug release for tumor-specific chemotherapy. Both in vitro and in vivo results indicated that the effective capture and magnetically guided transfer of CTCs to the primary tumor, as well as the multimodal tumor extermination performed by our FGPFAD nanosheet, significantly inhibited the primary tumor and its metastasis.

Multimodal obstruction of tumorigenic energy supply via bionic nanocarriers for effective tumor therapy.

Sufficient energy generation based on effective transport of nutrient via abundant blood vessels in tumor tissue and subsequent oxidative metabolism in mitochondria is critical for growth, proliferation and migration of tumor. Thus the strategy to cut off this transport pathway (blood vessels) and simultaneously close the power house (mitochondria) is highly desired for tumor treatment. Herein, we fabricated a bionic nanocarrier with core-shell-corona structure to give selective and effective tumor therapy via stepwise destruction of existed tumor vessel, inhibition of tumor angiogenesis and dysfunction of tumor mitochondria. The core of this bionic nanocarrier consists of combretastatin A4 phosphate (CA4P) and vitamin K2 (VK2) co-loaded mesoporous silica nanoparticle (MSNs), which is in charge of the vasculature destruction and mitochondrial dysfunction after cargos release. The N-tert-butylacrylamide (TBAM) and tri-sulfated N-acetylglucosamine (TSAG) shell served as artificial affinity reagent against vascular endothelial growth factor (VEGF) for angiogenesis inhibition. As to guarantee that these actions only happened in tumor, the hyaluronic acid (HA) corona was introduced to endow the nanocarrier with tumor targeting property and stimuli-responsiveness for accurate therapy. Both in vitro and in vivo results indicated that the CA4P/VK2-MSNs-TBAM/TSAG-HA (CVMMGH for short) nanocarrier combined well-controllable manipulation of tumor vasculature and tumor mitochondria to effectivly cut off the tumorigenic energy supply, which performed significant inhibition of tumor growth, demonstrating the great candidate of our strategy for effective tumor therapy.

The facile formation of hierarchical mesoporous silica nanocarriers for tumor-selective multimodal theranostics.

The combination of therapeutic and diagnostic functions in a single platform has aroused great interest due to the more optimal synergistic effects that can be obtained as compared to any single theranostic approach alone. However, current nanotheranostics are normally formed via complicated construction steps involving the pre-synthesis of each component and further conjugation via chemical bonds, which may cause low integration efficiency and limit production and applications. Herein, a tumor-targeting and tumor-responsive all-in-one nanoplatform based on mesoporous silica nanocarriers (MSNs) was fabricated via a facile approach utilizing efficient and nondestructive physical interactions for long-wavelength fluorescence imaging-guided synergistic chemo-catalytic-photothermal tumor therapy. The MSNs were endowed with these multimodal theranostics via a simple hydrothermal method after coordinating with Fe2+ and glutathione (GSH) to introduce ferroferric oxide and carbon dots in situ. The former acts as a photothermal agent and catalytic agent to generate local heat under 808 nm irradiation and also when toxic hydroxyl radicals (˙OH) are in contact with abundant hydrogen peroxide in cancer cells, while the latter participates in fluorescence imaging. After loading with paclitaxel (PTX), polyester and folic-acid-conjugated cyclodextrin were employed to serve as an esterase-sensitive gatekeeper controlling PTX release from the MSN pores and as a tumor-targeting agent for accurate therapy, respectively. As expected, the nanoplatform was efficiently taken up by tumor cells over healthy cells, and then, synergetic chemo-catalytic-photothermal therapy was performed, resulting in 5-fold greater apoptosis of tumor cells as compared to healthy cells under 808 nm irradiation. Moreover, in vivo data from tumor-bearing mouse models showed that tumors were significantly inhibited, and the survival rates of these mice increased to greater than 80% after 5 weeks of treatment with our nanoplatform. These therapeutic processes could be directly tracked via fluorescence imaging enabled by carbon dots and, therefore, our nanoplatform provides a promising theranostics approach for tumor treatment.

On-demand manipulation of tumorigenic microenvironments by nano-modulator for synergistic tumor therapy.

Proper manipulation of tumorigenic microenvironments has been considered as one of the most effective approaches for tumor therapy, which is still a challenge to be well performed. Herein, a nano-modulator was fabricated to manipulate the hypoxia, glucose, radicals and local temperature in tumor tissue as needed, which consists of hemoglobin (Hb) and ferric ion (Fe3+) co-conjugated polydopamine (PDA) as core, glucose oxidase (GOD) as shell, and folic acid (FA) modified polyethylene glycol (PEG) as corona. The PEG-FA corona not only protected Hb and GOD against protease in blood circulation, but serve as tumor targeting agent for tumor specific accumulation of the nano-modulator. The Hb is in charge of oxygen supply to reverse the hypoxic environment of tumor tissue, which promotes the function of GOD to achieve rapid glucose consumption and hydrogen peroxide generation. The polydopamine was employed to raise local temperature under NIR irradiation, meanwhile to continuously reduce Fe3+ to produce ferrous ions (Fe2+), which further catalyze hydrogen peroxide to cytotoxic hydroxyl radicals via Fenton reaction. Both in vitro and in vivo results showed excellent tumor inhibition and high survival rate of tumor-bearing mice after treatment by our nano-modulator, indicating this synergistic therapy via on-demand manipulation of various tumorigenic microenvironments could be a green approach for tumor treatment with high efficiency and minimum side effects.

T cell-depleting nanoparticles ameliorate bone loss by reducing activated T cells and regulating the Treg/Th17 balance.

Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women. Under chronic inflammatory conditions caused by estrogen deficiency, activated T cells contribute to elevated levels of proinflammatory cytokines, impaired osteogenic differentiation capabilities of bone marrow mesenchymal stem cells (BMMSCs), and disturbed regulatory T cell (Treg)/Th17 cell balance. However, therapeutic strategies that re-establish immune homeostasis in this disorder have not been well developed. Here, we produced T cell-depleting nanoparticles (TDNs) that ameliorated the osteopenia phenotype and rescued the osteogenic deficiency of BMMSCs in ovariectomized (OVX) mice. TDNs consist of monocyte chemotactic protein-1 (MCP-1)-encapsulated mesoporous silica nanoparticles as the core and Fas-ligand (FasL) as the corona. We showed that the delicate design of the TDNs enables rapid release of MCP-1 to recruit activated T cells and then induces their apoptosis through the conjugated FasL both in vitro and in vivo. Apoptotic signals recognized by macrophages help skew the Treg/Th17 cell balance and create an immune tolerant state, further attenuating the osteogenic deficiency of BMMSCs and the osteopenia phenotype. Mechanistically, we found that the therapeutic effects of TDNs were partially mediated by apoptotic T cell-derived extracellular vesicles (ApoEVs), which promoted macrophage transformation towards the M2 phenotype. These findings demonstrate that TDNs may represent a promising strategy for treating osteoporosis and other immune disorders.

Modular immune-homeostatic microparticles promote immune tolerance in mouse autoimmune models.

The therapeutic goal for autoimmune diseases is disease antigen-specific immune tolerance without nonspecific immune suppression. However, it is a challenge to induce antigen-specific immune tolerance in a dysregulated immune system. In this study, we developed immune-homeostatic microparticles (IHMs) that treat multiple mouse models of autoimmunity via induction of apoptosis in activated T cells and reestablishment of regulatory T cells. Specifically, in an experimental model of colitis, IHMs rapidly released monocyte chemotactic protein-1 after intravenous administration, which recruited activated T cells and then induced their apoptosis by conjugated Fas ligand on the IHM surface. This triggered professional macrophages to ingest apoptotic T cells and produce high quantities of transforming growth factor-ß, which drove regulatory T cell differentiation. Furthermore, the modular design of IHMs allowed IHMs to be engineered with the autoantigen peptides that can reduce disease in an experimental autoimmune encephalomyelitis mouse model and a nonobese diabetic mouse model. This was accomplished by sustained release of the autoantigens after induction of T cell apoptosis and transforming growth factor-ß production by macrophages, which promoted to establish an immune tolerant environment. Thus, IHMs may be an efficient therapeutic strategy for autoimmune diseases through induction of apoptosis and reestablishment of tolerant immune responses.

Treatment of infarcted heart tissue via the capture and local delivery of circulating exosomes through antibody-conjugated magnetic nanoparticles.

The systemic biodistribution of endogenous extracellular vesicles is central to the maintenance of tissue homeostasis. Here, we show that angiogenesis and heart function in infarcted heart tissue can be ameliorated by the local accumulation of exosomes collected from circulation using magnetic nanoparticles. The nanoparticles consist of a Fe3O4 core and a silica shell that is decorated with poly (ethylene glycol) conjugated through hydrazone bonds to two types of antibody, which bind either to CD63 antigens on the surface of extracellular vesicles or to myosin-light-chain surface markers on injured cardiomyocytes. On application of a local magnetic field, accumulation of the nanoparticles and cleavage of the hydrazone bonds under the acidic pH of injured cardiac tissue lead to the local release of the captured exosomes. In rabbit and rat models of myocardial infarction, the magnetic-guided accumulation of captured CD63-expressing exosomes in infarcted tissue led to reductions in infarct size as well as improved left-ventricle ejection fraction and angiogenesis. The approach could be used to manipulate endogenous exosome biodistribution for the treatment of other diseases.

Nanocomposite hydrogel with NIR/magnet/enzyme multiple responsiveness to accurately manipulate local drugs for on-demand tumor therapy.

Chemotherapy is one of the most commonly utilized approaches to treat malignant tumor. However, the well-controlled chemotherapy able to accurately manipulate local drugs for on-demand tumor treatment is still a challenge. Herein, a magnet and light dual-responsive hydrogel combining thermosensitive poly(N-acryloyl glycinamide) (PNAGA), doxorubicin (DOX) loaded and polyester (PE) capped mesoporous silica nanocarriers (MSNs) as well as Fe3O4 nanoparticles (Fe3O4 NPs) grafted graphene oxide (GO) was fabricated to address above issue. The Fe3O4 NPs and GO respectively serve as magnetothermal agent and photothermal agent to perform hyperthermia, meanwhile to generate chain motion of PNAGA with varying degrees under different conditions of magnetic field and/or NIR irradiation. This strategy not only allowed the gel-sol transition of the hydrogel by prior heating for tumor injection, but performed controllable release routes of DOX-MSNs-PE (DMP for short) nanocarriers to meet various requirements from different patients and the changing states of tumor. Furthermore, these escaped DMP nanocarriers could be taken by surrounding tumor cells, and then deliver their drug to these cells after rapid hydrolysis of the PE cap triggered by esterase, resulting in accurate chemotherapy. Both in vitro and in vivo results indicated that the PNAGA-DMP-Fe3O4@GO hydrogel combining well-controllable chemotherapy and hyperthermia can eliminate more than 90% tumor cells and effectively inhibit the tumor growth in mice model, demonstrating the great candidate of our hydrogel for accurate tumor therapy.

Substrate-independent polymer coating with stimuli-responsive dexamethasone release for on-demand fibrosis inhibition.

Tissue fibrosis caused by implantation of tissue engineering scaffolds is an urgent problem in clinical research. In this work, a substrate-independent coating with on-demand release of an antifibrotic drug has been fabricated to effectively address this issue. This coating was formed through a substrate-independent layer-by-layer (LBL) technique via a cationic polyelectrolyte (poly-diallyldimethylammonium, PDDA) and an anionic polyelectrolyte (poly-styrenesulfonate, PSS), where parts of PSS and PDDA were physically replaced by carboxyl functionalized polyethylene glycol grafted onto antifibrotic drug dexamethasone (DEX-PEG-COOH). Considering the easy generation of local inflammation after implantation, an ester bond was designed between PEG-COOH and DEX. Therefore, the overexpressed esterase under inflammatory conditions hydrolyzes the ester bond and thereby releases DEX from the film to inhibit fibrosis occurring in the tissue repair process. The in vivo capacity of this coating to restrain tissue fibrosis was investigated by a skin defect model using porous polycaprolactone (PCL) scaffolds as substrates. The experimental results showed that the fibrosis-related proteins (Col-I, TGF-ß and fibronectin) and the infiltration of myofibroblasts (α-SMA) of skin tissues in the coated PCL scaffold group were significantly lower than those in the blank control group and pure PCL scaffold group. Moreover, the histological evaluations showed that the coating group could significantly decrease the deposition of collagen and meanwhile promote the partial regeneration of skin appendages. These results successfully demonstrate that the universal coating prepared with a simple protocol would be an effective strategy to address the fibrosis issues during tissue engineering.

Chimeric apoptotic bodies functionalized with natural membrane and modular delivery system for inflammation modulation.

Engineered extracellular vesicles (EVs) carrying therapeutic molecules are promising candidates for disease therapies. Yet, engineering EVs with optimal functions is a challenge that requires careful selection of functionally specific vesicles and a proper engineering strategy. Here, we constructed chimeric apoptotic bodies (cABs) for on-demand inflammation modulation by combining pure membrane from apoptotic bodies (ABs) as a bioconjugation/regulation module and mesoporous silica nanoparticles (MSNs) as a carrier module. MSNs were preloaded with anti-inflammatory agents (microRNA-21 or curcumin) and modified with stimuli-responsive molecules to achieve accurate cargo release at designated locations. The resulting cABs actively target macrophages in the inflammatory region and effectively promote M2 polarization of these macrophages to modulate inflammation due to the synergistic regulatory effects of AB membranes and the intracellular release of preloaded cargos. This work provides strategies to arbitrarily engineer modular EVs that integrate the advantages of natural EVs and synthetic materials for various applications.

A tumor-targeted nanoplatform with stimuli-responsive cascaded activities for multiple model tumor therapy.

Herein, a rambutan-like nanocomplex (PDA-SNO-GA-HA-DOX, PSGHD for short) was designed to enable effective and accurate tumor therapy. The PSGHD nanocomplex consists of an S-nitrosothiol-functionalized polydopamine (PDA-SNO) core and a gambogic acid-derivatized hyaluronic acid (HA-GA) shell with doxorubicin (DOX) as the cargo. Due to the HA section, the PSGHD nanocomplex can be rapidly and selectively internalized by tumor cells instead of healthy cells in 12 h of co-incubation. After that, the internalized PSGHD nanocomplex is able to gradually release both DOX (agent for chemotherapy) and GA (agent for enhancing thermal damage) under different tumor-specific physiological conditions (low pH and rich HAase). When 808 nm NIR radiation was employed, the PSGHD nanocomplex further demonstrated excellent photothermal conversion to increase the local temperature over 43 °C and convert SNO to nitric oxide (NO, an agent for decreasing drug-efflux). Based on the synergistic effects of NO/DOX and GA/heat, the PSGHD nanocomplex simultaneously achieved tumor-specific low-drug-efflux chemotherapy and low-temperature photothermal therapy, resulting in an eight-fold apoptosis of tumor cells over normal cells under NIR radiation. In vivo data from mouse models further showed that the PSGHD nanocomplex can completely inhibit tumor growth and significantly prolong the survival rate of tumor bearing mice in 50 days, demonstrating the high efficiency of the PSGHD nanocomplex for tumor therapy.

Intracellular Enzyme-Triggered Assembly of Amino Acid-Modified Gold Nanoparticles for Accurate Cancer Therapy with Multimode.

Multiple amino acid (glutamine and lysine)-modified gold nanoparticles a with pH-switchable zwitterionic surface were fabricated through coordination bonds using ferrous iron (Fe2+) as bridge ions, which are able to spontaneously and selectively assemble in tumor cells for accurate tumor therapy combining enzyme-triggered photothermal therapy and H2O2-dependent catalytic medicine. These gold nanoparticles showed electric neutrality at pH 7.4 (hematological system) to prevent endocytosis of normal cells, which could be positively charged at pH 6.8 (tumor microenvironment) to promote the endocytosis of tumor cells to these nanoparticles, performing great tumor selectivity. After cell uptake, the specific enzyme (transglutaminase) in tumor cells would catalyze the polymerization of glutamine and lysine to cause the intracellular assembly of these gold nanoparticles, resulting in an excellent photothermal property for accurate tumor therapy. Moreover, the Fe2+ ion could decompose excess hydrogen peroxide (H2O2) in tumor cells via the Fenton reaction, resulting in a large amount of hydroxyl radicals (·OH). These radicals would also cause tumor cell damage. This synergetic therapy associating with high tumor selectivity generated an 8-fold in vitro cytotoxicity against tumor cells compared with normal cells under 48 h incubation with 10 min NIR irradiation. Moreover, in vivo data from tumor-bearing nude mice models showed that tumors can be completely inhibited and gradually eliminated after multimode treatment combining catalytic medicine and photothermal therapy for 3 weeks. This system takes advantage of three tumor microenvironment conditions (low pH, enzyme, and H2O2) to trigger the therapeutic actions, which is a promising platform for cancer therapy that achieved prolonged circulation time in the blood system, selective cellular uptake, and accurate tumor therapy in multiple models.

Substrate-Independent Coating with Persistent and Stable Antifouling and Antibacterial Activities to Reduce Bacterial Infection for Various Implants.

Implantation of biomedical devices accompanying infections has caused severe problems to public health that require feasible solutions. In this study, a simple approach is reported to fabricate a antimicrobial and antifouling dual-functional coating. This coating consists of a substrate-independent layer-by-layer (LBL) film formed by poly (diallyldimethylammonium) (PDDA) and poly (styrenesulfonate) (PSS), where parts of PSS and PDDA are physically substituted by hetero-bifunctional polyethylene glycol (PEG) ending with a carboxyl group and antimicrobial peptide (ε-Poly-l-lysine, ε-PL). This design (ε-PL-PEG-(PDDA/PSS)9 coating) exhibits not only potent antimicrobial activity against Gram-positive/negative bacteria but also superior antifouling activity on various substrates, including glass and plastic. Moreover, the antifouling and antibacterial performance can be maintained for a longer period of time under physiological environments even after physical damage of the surface due to the homogeneous interspersion and free migration of ε-PL-PEG-COOH in the LBL film. This allows the supplement of these molecules to the surface against molecule loss during usage. Both in vitro and in vivo (rodent subcutaneous infection model) studies show obvious reduction of the bacteria on the coated substrate and in the surrounding tissues with up to 3.2-log reduction, even after repeated usage. The inflammation around the implantation area is also significantly inhibited.

Injectable colloidal hydrogel with mesoporous silica nanoparticles for sustained co-release of microRNA-222 and aspirin to achieve innervated bone regeneration in rat mandibular defects.

Nerve fibers and vessels play important roles in bone formation, and inadequate innervation in the bone defect area can delay the regeneration process. However, there are few studies aiming to promote innervation to engineer bone formation. Here, we report the development of an injectable thermoresponsive mesoporous silica nanoparticle (MSN)-embedded core-shell structured poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)-b-poly(N-isopropylacrylamide) (PEG-PLGA-PNIPAM) hydrogel for localized and long-term co-delivery of microRNA-222 and aspirin (ASP) (miR222/MSN/ASP hydrogel). ASP was found to stimulate bone formation as previously reported, and miR222 induced human bone mesenchymal stem cell differentiation into neural-like cells through Wnt/ß-catenin/Nemo-like kinase signaling. In a rat mandibular bone defect, injection of the co-delivered MSN hydrogel resulted in neurogenesis and enhanced bone formation, indicating that the present injectable miR222- and ASP-co-delivering colloidal hydrogel is a promising material for innervated bone tissue engineering.

Fabrication of Self-Healing Hydrogels with On-Demand Antimicrobial Activity and Sustained Biomolecule Release for Infected Skin Regeneration.

Microbial infection has been considered as one of the most critical challenges in bioengineering applications especially in tissue regeneration, which engenders severe threat to public health. Herein, a hydrogel performing properties of rapid self-healing, on-demand antibiosis and controlled cargo release was fabricated by a simple assembly of Fe complex as the cross-linker and hyaluronic acid as the gel network. This hydrogel is able to locally degrade and release Fe3+ to kill bacteria as needed because of hyaluronidase excreted by surrounding bacteria, resulting in efficient antibacterial activity against different types of bacteria. The sustained release property of certain types of growth factors was also observed from this hydrogel owing to its dense network. Moreover, this hydrogel could repeatedly heal itself in minutes because of the coordination interaction between Fe3+ and COOH, exhibiting good potential in bioengineering applications on the exposed tissue, where the materials are easily damaged during daily life. When topically applied onto damaged mouse skin with infection of Staphylococcus aureus, the hydrogel is able to inhibit microbial infections, meanwhile promoting cutaneous regeneration, which formed new skin with no inflammation within a 10 day treatment. These results demonstrate the potential application of this self-healing hydrogel for the integrated therapy of antibiosis and tissue regeneration.

One-pot preparation of polymer microspheres with different porous structures to sequentially release bio-molecules for cutaneous regeneration.

Herein, we reveal a double emulsion method combining the sol-gel method to prepare poly(lactic-co-glycolic acid) microspheres with different porous structures for sequential release of two types of biomolecules. By controlling the ripening time of the emulsion, multiple interconnected chambers could be easily chosen to be either embedded in microspheres or opened to the surface. These two types of microspheres exhibited different kinetics for the release of both small molecules and proteins, where the release from microspheres with open pores (5 day over 90%) was much faster than the release from microspheres with embedded pores (25 day over 90%). After loading with interleukin-4 (IL-4) and melatonin, these microspheres were further encapsulated in a sodium alginate hydrogel to form a patch for cutaneous regeneration. The prepared patch was able to recruit alternatively activated (M2) macrophages in the early stage (fast release of IL-4) and promote the growth of blood vessels in the long term (slow release of melatonin), resulting in significantly enhanced cutaneous regeneration. These results also demonstrate the potential of this novel delivery system to deliver multiple therapeutics and achieve synergistic effects.

Dual responsive hydrogels based on functionalized mesoporous silica nanoparticles as an injectable platform for tumor therapy and tissue regeneration.

To achieve effective tumor therapy and regenerate new tissue from defects formed by tumor atrophy, a dual responsive hydrogel integrating the stepwise delivery of anti-tumor drugs/growth factors and pH/thermo induced structural transformation is developed, based on polymer (poly N-isopropylacrylamide (PNIPAM) and polyacrylic acid (PAA)) functionalized mesoporous silica nanoparticles (MSNs). Due to the thermally responsive tangle between PNIPAM chains and the pH triggered hydrogen bonds in PAA chains, these injectable MSNs would immediately switch from nanoparticles to compact hydrogels in a tumor environment (37.5 °C, pH 6.8), where the concentrated network structure in the hydrogel is in charge of the loading and local delivery of anti-tumor drugs. The MSNs serve as nanocarriers for growth factors, which are localized by crosslinked networks. The sustained release of growth factors only occurred with the cleavage of hydrogen bonds in PAA chains, which is triggered by the pH increase to 7.4 after the cure of the tumor. Moreover, the hydrogen bond cleavage would also cause the swelling of the hydrogel, which not only fills the defects but generates plenty of cell-level pores, resulting in an excellent scaffold for attachment and proliferation of healthy cells. Therefore, the dual responsive MSN-hydrogels offer a promising strategy for sequential tumor therapy and tissue regeneration.