In the U.S., 30% of adults suffer joint pain, most commonly in the knee, which severely limits mobility and is often attributed to injury of cartilage and underlying bone in the joint. Current treatment methods such as microfracture result in less resilient fibrocartilage with eventual failure; autografting can cause donor site morbidity and poor integration. To overcome drawbacks in treatment, tissue engineers can design cell-instructive biomimetic scaffolds using biocompatible materials as alternate therapies for osteochondral defects. Nanofibrous poly (L-lactic acid) (PLLA) scaffolds of uniform, spherical, interconnected and well-defined pore sizes that are fabricated using a thermally-induced phase separation and sugar porogen template method create an extracellular matrix-like environment which facilitates cell adhesion and proliferation. Herein we report that chondrogenesis and endochondral ossification of rabbit and human bone marrow stromal cells (BMSCs) can be controlled by scaffold pore architecture, particularly pore size. Small-pore scaffolds support enhanced chondrogenic differentiation in vitro and cartilage formation in vivo compared to large-pore scaffolds. Endochondral ossification is prevented in scaffolds with very small pore sizes; pore interconnectivity is critical to promote capillary ingrowth for mature bone formation. These results provide a novel strategy to control tissue regenerative processes by tunable architecture of macroporous nanofibrous scaffolds.

Tissue-engineered blood vessels (TEBVs) are promising in the replacement of diseased vascular tissues. However, it remains a great challenge to obtain a sufficient number of functional smooth muscle cells (SMCs) in a clinical setting to construct patient-specific TEBVs. In addition, it is critical to develop a scaffold to accommodate these cells and retain their functional phenotype for the regeneration of TEBVs. In this study, human induced pluripotent stem cells (iPSCs) were established from primary human aortic fibroblasts, and characterized with the pluripotency markers expression and cells’ capabilities to differentiate into all three germ layer cells. A highly efficient method was then developed to induce these human iPSCs into proliferative SMCs. After multiple times of expansion, the expanded SMCs retained the potential to be induced into the functional contractile phenotype of mature SMCs, which was characterized by the contractile response to carbachol treatment, up-regulation of specific collagen genes under transforming growth factor β1 treatment, and up-regulation of specific matrix metalloproteinase genes under cytokine stimulation. We also developed an advanced macroporous and nanofibrous (NF) poly(L-lactic acid) (PLLA) scaffold with suitable pore size and interpore connectivity to seed these human iPSC-derived SMCs and maintain their differentiated phenotype. Subcutaneous implantation of the SMC-scaffold construct in nude mice demonstrated vascular tissue formation, with robust collagenous matrix deposition inside the scaffold and the maintenance of differentiated SMC phenotype. Taken together, this study established an exciting approach towards the construction of patient-specific TEBVs. We established patient-specific human iPSCs, derived proliferative SMCs fore expansion, turned on their mature contractile SMC phenotype, and developed an advanced scaffold for these cells to regenerate vascular tissue in vivo.

In addition to T cells' roles in immune response and autoimmune diseases, certain types of T cells, called regulatory T cells (Tregs), play important roles in microenvironment modulation for resolution and tissue regeneration. However, there are currently few options available other than introducing more Tregs or immunosuppressive drugs to locally enrich Tregs. Herein, poly(l-lactic acid) (PLLA) nanofibrous spongy microspheres (NF-SMS), PLLA/polyethylene glycol (PEG) co-functionalized mesoporous silica nanoparticles (MSN), and poly(lactic acid- co-glycolic acid) microspheres (PLGA MS) are integrated into one multibiologic delivery vehicle for in situ Treg manipulation, where the MSNs and PLGA MS were utilized to distinctly release IL-2/TGF-β and miR-10a to locally recruit T cells and stimulate their differentiation into Tregs, while PLLA NF-SMS serve as an injectable scaffold for the adhesion and proliferation of these Tregs. In a mouse model of periodontitis, the injectable and biomolecule-delivering PLLA NF-SMS lead to Treg enrichment, expansion, and Treg-mediated immune therapy against bone loss. This system can potentially be utilized in a wide variety of other immune and regenerative therapies.

A core-satellite nanotheranostic agent with pH-dependent photothermal properties, pH-triggered drug release, and H 2 O 2 -induced catalytic generation of radical medicine is fabricated to give a selective and effective tumor medicine with three modes of action. The nanocomplex (core-satellite mesoporous silica-gold nanocomposite) consists of amino-group-functionalized mesoporous silica nanoparticles (MSN-NH 2 ) linked to L-cysteinederivatized gold nanoparticles (AuNPs-Cys) with bridging ferrous iron (Fe 2+ ) ions. The AuNPs-Cys serve as both removable caps that control drug release (doxorubicin) and stimuli-responsive agents for selective photothermal therapy. Drug release and photothermal therapy are initiated by the cleavage of Fe 2+ coordination bonds at low pH and the spontaneous aggregation of the dissociated AuNPs-Cys. In addition, the Fe 2+ is able to catalyze the decomposition of hydrogen peroxide abundant in cancer cells by a Fentonlike reaction to generate high-concentration hydroxyl radicals (·OH), which then causes cell damage. This system requires two tumor microenvironment conditions (low pH and considerable amounts of H 2 O 2 ) to trigger the three therapeutic actions. In vivo data from mouse models show that a tumor can be completely inhibited after two weeks of treatment with the combined chemo-photothermal method; the data directly demonstrate the efficiency of the MSN-Fe-AuNPs for tumor therapy.

Mesoporous silica nanocarriers with pH-switchable antifouling zwitterionic surface, enzyme responsive drug release properties and blue fluorescence are reported. Prolonged circulation in the blood system with zero premature release as well as efficient cellular uptake and intracellular drug release in tumor tissue are achieved.

An injectable hydrogel was developed using mesoporous silica nanoparticles to co-deliver miR222 and aspirin, osteogenesis was enhanced by stimulating innervation.

Herein, we report a facile fabrication of a polymer (azobenzene and α-cyclodextrin-functionalized hyaluronic acid) and gold nanobipyramids (AuNBs) conjugated mesoporous silica nanoparticles (MSNs) to be used as an injectable drug delivery system for sustained cancer treatment. Because of the specific affinity between the hyaluronic acid (HA) on MSNs and the CD44 antigen overexpressed on tumor cells, the MSNs can selectively attach to tumor cells. The nanocomposite material then exploits thermoresponsive interactions between α-cyclodextrin and azobenzene, and the photothermal properties of gold nanobipyramids, to in situ self-assemble into a hydrogel under near-infrared (NIR) radiation. Upon gelation, the drug (doxorubicin)-loaded MSNs carriers were enclosed in the HA network of the hydrogel, whereas further degradation of the HA in the hydrogel due to the upregulation of hyaluronidase (HAase) around the tumor tissue will result in the release of MSNs from the hydrogel, which can then be taken by tumor cells and deliver their drug to the cell nuclei. This design is able to provide a microenvironment with rich anticancer drugs in, and around, the tumor tissue for time periods long enough to prevent the recrudescence of the disease. The extra efficacy that this strategy affords builds upon the capabilities of conventional therapies.

Tissue-engineered blood vessels (TEBVs) are promising in regenerating a live vascular replacement. However, the vascular cell source is limited, and it is crucial to develop a scaffold that accommodates new type of vascular progenitor cells and facilitates in vivo lineage specification of the cells into functional vascular smooth muscle cells (VSMCs) to regenerate vascular tissue. In the present study, integration-free human induced pluripotent stem cells (hiPSCs) were established from patient peripheral blood mononuclear cells through episomal vector nucleofection of reprogramming factors. The established hiPSCs were then induced into mesoderm-originated cardiovascular progenitor cells (CVPCs) with a highly efficient directed lineage specification method. The derived CVPCs were demonstrated to be able to differentiate into functional VSMCs. Subcutaneous implantation of CVPCs seeded on macroporous nanofibrous poly(l-lactide) scaffolds led to in vivo VSMC lineage specification and matrix deposition inside the scaffolds. In summary, we established integration-free patient-specific hiPSCs from peripheral blood mononuclear cells, derived CVPCs through directed lineage specification, and developed an advanced scaffold for these progenitor cells to further differentiate in vivo into VSMCs and regenerate vascular tissue in a subcutaneous implantation model. This study has established an efficient patient-specific approach towards in vivo regeneration of vascular tissue.