There is a growing interest in the development of tissue engineering (TE) therapies to repair damaged bone. Among the scaffolds for TE applications, injectable hydrogels have demonstrated great potential as three-dimensional cell cultures in bone TE, owing to their high water content, porous structure that allows cell transplantation and proliferation, similarity to the natural extracellular matrix and ability to match irregular defects. We investigated whether fibrin-based hydrogels capable of transducing near infrared (NIR) energy into heat can be employed to lead bone repair. Hollow gold nanoparticles with a plasmon surface band absorption at ∼750 nm, a NIR wavelength within the so called “tissue optical window”, were used as fillers in injectable fibrin-based hydrogels. These composites were loaded with genetically-modified cells harbouring a heat-activated and rapamycin-dependent gene circuit to regulate transgenic expression of the reporter gene firefly luciferase (fLuc). NIR-responsive cell constructs were injected to fill a 4 mm diameter critical-sized defect (CSD) in the parietal bone of mouse calvaria. NIR-irradiation in the presence of rapamycin triggered a pattern of fLuc activity that faithfully matched the illuminated area of the implanted hydrogel. Having shown that this platform can control the expression of a transgene product, we tested its effectiveness on regulating the secretion of transgenic bone morphogenetic protein 2 (BMP-2) from NIR-responsive hydrogels implanted in CSD. The spatiotemporal pattern of transgenic BMP-2 secretion induced by NIR-irradiation in the presence of rapamycin significantly stimulated bone regeneration from the edge of osteotomy in the CSD practiced, validating the therapeutic approach.

As near-infrared (NIR) photothermal agents, copper sulfide nanoparticles (CuSNP) offer several advantages over plasmonic gold nanoparticles (GNP), the most widely used photothermal nanotransducers in biomedical applications. CuSNP exhibit strong optical absorption at NIR wavelengths (650–1100 nm) and convert it into heat due excitation of electronic transitions or plasmonic photoexcitation. In contrast with GNP, CuSNP are degradable, readily prepared, inexpensive to produce, efficiently cleared from the body and their photothermal efficiency is less sensitive to the dielectric constant of the surrounding medium. We explored the feasibility of CuSNP to function as degradable NIR nanotransducers within fibrin-based cellular scaffolds, paying great attention to the stability and photothermal efficiency of the composite. We tested in vitro and in vivo whether NIR-responsive fibrin hydrogels comprising CuSNP (CuSNP hydrogels) are reliable platforms for triggering transgene expression in cells harboring a gene circuit activatable by heat and dependent of rapamycin. NIR laser irradiation of the CuSNP hydrogels increased local temperature and, in the presence of rapamycin, triggers the gene switch based on the promoter of the highly heat-inducible HSP70B gene (HSPA7). After implantation of such a cell-containing CuSNP hydrogel, transgenic expression can be remotely triggered by NIR-irradiation. Interestingly, we found that CuSNP hydrogels induce remodeling activity in stem cells and stimulate an angiogenic response. In short, CuSNP hydrogels offer compelling features for tissue engineering applications, as fully degradable implants with enhanced integration capacity in host tissues that can provide for remote control in the deployment of therapeutic gene products.