Organic semiconducting polymer amphiphile for near-infrared-II light-triggered phototheranostics.

Development of near-infrared-II (NIR-II) light responsive nano-agents with high photothermal stability, high photothermal conversion efficiency (PCE), and excellent biocompatibility for photoacoustic (PA) imaging-guided photothermal therapy (PTT) is of tremendous significance. In spite of the superiority of organic semiconducting polymer nanoparticles (OSPNs) in PA imaging-guided PTT, the limited absorption in the first NIR (NIR-I) window and metastable nanostructure of OSPNs resulting from commonly used preparation methods based on nanoprecipitation or reprecipitation compromise their in vivo phototheranostic performance. Herein we design and synthesize a novel NIR-II absorbing organic semiconducting polymer amphiphile (OSPA) to enhance the structural stability of OSPNs. With prominent optical properties, low toxicity, and a suitable size, OSPA not only efficiently labels and kills cancer cells under NIR-II irradiation but also accumulates at the tumor of living mice upon intravenous injection, allowing efficient NIR-II light-triggered phototheranostics toward tumor. The developed OSPA has promising potential for fabricating multifunctional nanoplatforms to enable multimodal theranostics.

Nanolayered hybrid mediates synergistic co-delivery of ligand and ligation activator for inducing stem cell differentiation and tissue healing.

Cellular behaviors, such as differentiation, are regulated by complex ligation processes involving cell surface receptors, which can be activated by various divalent metal cations. The design of nanoparticle for co-delivery of ligand and ligation activator can offer a novel strategy to synergistically stimulate ligation processes in vivo. Here, we present a novel layered double hydroxide (LDH)-based nanohybrid (MgFe-Ado-LDH), composed of layered MgFe hydroxide nanocarriers sandwiching the adenosine cargo molecule, maintained through an electrostatic balance, to co-deliver the adenosine (Ado) ligand from the interlayer spacing and the Mg2+ ion (ligation activator) through the dissolution of the MgFe nanocarrier itself. Our findings demonstrate that the MgFe-Ado-LDH nanohybrid promoted osteogenic differentiation of stem cells through the synergistic activation of adenosine A2b receptor (A2bR) by the dual delivery of adenosine and Mg2+ ions, outperforming direct supplementation of adenosine alone. Furthermore, the injection of the MgFe-Ado-LDH nanohybrid and stem cells embedded within hydrogels promoted the healing of rat tibial bone defects through the rapid formation of fully integrated neo-bone tissue through the activation of A2bR. The newly formed bone tissue displayed the key features of native bone, including calcification, mature tissue morphology, and vascularization. This study demonstrates a novel and effective strategy of bifunctional nanocarrier-mediated delivery of ligand (cargo molecule) and activation of its ligation to receptor by the nanocarrier itself for synergistically inducing stem cell differentiation and tissue healing in vivo, thus offering novel design of biomaterials for regenerative medicine.

Enhanced MSC chondrogenesis following delivery of TGF-ß3 from alginate microspheres within hyaluronic acid hydrogels in vitro and in vivo.

Mesenchymal stem cells (MSCs) are being recognized as a viable cell source for cartilage repair and members of the transforming growth factor-beta (TGF-ß) superfamily are a key mediator of MSC chondrogenesis. While TGF-ß mediated MSC chondrogenesis is well established in in vitro pellet or hydrogel cultures, clinical translation will require effective delivery of TGF-ßs in vivo. Here, we investigated the co-encapsulation of TGF-ß3 containing alginate microspheres with human MSCs in hyaluronic acid (HA) hydrogels towards the development of implantable constructs for cartilage repair. TGF-ß3 encapsulated in alginate microspheres with nanofilm coatings showed significantly reduced initial burst release compared to uncoated microspheres, with release times extending up to 6 days. HA hydrogel constructs seeded with MSCs and TGF-ß3 containing microspheres developed comparable mechanical properties and cartilage matrix content compared to constructs supplemented with TGF-ß3 continuously in culture media, whereas constructs with TGF-ß3 directly encapsulated in the gels without microspheres had inferior properties. When implanted subcutaneously in nude mice, constructs containing TGF-ß3 microspheres resulted in superior cartilage matrix formation when compared to groups without TGF-ß3 or with TGF-ß3 added directly to the gel. However, calcification was observed in implanted constructs after 8 weeks of subcutaneous implantation. To prevent this, the co-delivery of parathyroid hormone-related protein (PTHrP) with TGF-ß3 in alginate microspheres was pursued, resulting in partially reduced calcification. This study demonstrates that the controlled local delivery of TGF-ß3 is essential to neocartilage formation by MSCs and that further optimization is needed to avert the differentiation of chondrogenically induced MSCs towards a hypertrophic phenotype.

Influence of chondroitin sulfate on the biochemical, mechanical and frictional properties of cartilage explants in long-term culture.

A recent study [Basalo et al., 2007. Chondroitin sulfate reduces the friction coefficient of articular cartilage. J. Biomech. 40(8), 1847-1854] has shown that the friction coefficient of bovine articular cartilage is reduced significantly by the supplementation of chondroitin sulfate (CS) at a concentration of 100mg/ml. This result suggests that intra-articular injection of CS may be used as a prophylactic treatment against the progression of osteoarthritis. The objective of this study was to test the hypothesis that long-term culture of cartilage explants in CS produces no adverse mechanical, biochemical, or cytotoxic effects, while reducing the friction coefficient relative to the control group. Long-term cultures of live bovine articular cartilage explants were performed with incubation in media containing CS of three different concentrations (0, 10 and 100mg/ml). Frictional tests (cartilage-on-glass) were performed under constant stress (0.5MPa) for 3600s and the time-dependent friction coefficient was measured. Samples incubated in a 100mg/ml of CS solution exhibited a significantly lower equilibrium friction coefficient than the control (0.05+/-0.01 vs. 0.18+/-0.02 on Day 0, 0.04+/-0.01 vs. 0.14+/-0.04 on Day 7 and 0.04+/-0.01 vs. 0.15+/-0.06 on Day 14). Samples incubated in 10mg/ml of CS did not exhibit any significant decrease in the friction coefficient. Cell viability and DNA content were maintained in all groups. However, after 28 days of culture, the Young's modulus and glycosaminoglycan content of explants incubated in 100mg/ml of CS decreased to 5% and 40% of their initial levels, respectively. Based on this adverse outcome the hypothesis of this study is rejected, dampening our enthusiasm for the use of intra-articular CS injections as a prophylactic treatment in osteoarthritis.