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In addition to natural and synthetic polymers, inorganic materials, such as metal oxides (MOs), metal nanoparticles (NPs), and carbon-based nanomaterials (NMs) are being intensively studied for TE applications [21]. Layered silicate nanoclays have been widely pursued for dermatological and musculoskeletal applications [22,23]. Similarly, carbon-based NMs have been exploited as fillers for TE applications owing to their chemical stability, low coefficient of friction, good mechanical properties, heat and wear resistance, high electrical conductivity, and hardness [24,25,26]. On the other hand, MOs, including bioceramics, bio-glasses (BGs), and magnetic NPs have also been exploited for TE. Of these, bioceramics have been shown to induce biomineralization due to their excellent osteo-conductivity, chemical resistance, and durability. Bioceramics can be further classified as biologically inert, bioactive, or bioresorbable, which are mainly based on their interaction with the host tissues in vivo [27]. While biologically inert ceramics are physically and chemically stable and do not interact with the tissues, bioactive ceramics can repair, replace and regenerate tissues. On the other hand, bioresorbable ceramics gradually degrade in vivo without inducing obvious toxicity risks. Metal NPs are also widely exploited in TE due to their high stability and ease of synthesis. Different types of metal NPs, such as gold (Au), silver (Ag), iron (Fe), aluminum (Al), nickel (Ni), copper (Cu), strontium (Sr), and zirconium (Zr) [28] have been shown to play a pivotal role in regulating cellular behavior as well as promoting tissue regeneration. Since inorganic NMs exhibit unique physico-chemical and mechanical properties, their introduction into TE scaffolds may impart bio-functionality as well as improve elasticity and resistance to mechanical stress. Consequently, bio-scaffolds comprised of inorganic/organic hybrids may help realize customized biomechanical properties as well as sufficient bioresorbability [29].

Yang et al. [82] developed nanofibrous hydrogels (NFH) by combining flexible SiO2 nanofibers along with ionically-crosslinked alginate. As compared to the hydrogels composed of pristine alginate, NFH exhibited remarkably higher mechanical properties, which were attributable to flexible SiO2 nanofibers. The NFH showed a plastic deformation value of only 9.5% after 1000 compression cycles at 50% strain (Figure 3A iii). In addition, the Al-alginate was uniformly wrapped around the surface of the SiO2 nanofibers, which further improved the water content of NFH for up to 99.8 wt.% (Figure 3A ii). This highly hydrated and porous nanofibrous structure allowed NFH to maintain a sensitive shape memory recovery function as well as imparted injectability characteristics (Figure 3A i). The combination of highly sensitive responsiveness of NFH with the current and pressure may further open a window of opportunity for research in electrical/pressure-stimulated TE scaffolds (Figure 3A vi. Despite these encouraging results, the biocompatibility of these NFH hydrogels as well as their long-term in vivo implantation yet remains to be explored.

Since inorganic NMs exhibit good physico-chemical properties and bioactivity, they can significantly improve the performance of scaffolds and may also have a direct impact on the growth of different types of cells. Since inorganic ions have been shown to be the important regulators of angiogenesis and osteogenesis, precisely-designed inorganic NMs may be harnessed to simultaneously promote angiogenesis and antibacterial effects as well as scavenge ROS [120] for tissue repair. The strategy of introducing inorganic NMs may further widen the application prospect of biomaterials. While an array of inorganic NMs have already been harnessed to afford functional scaffolds for TE, further research is warranted to better delineate their effect to promote tissue repair. Similarly, whereas composite nanofibers doped with inorganic NMs have been widely harnessed for musculoskeletal tissue repair, their application for other injury/tissue types, such as skin, heart, ischemia, muscle, and nerve may further be exploited. The precise design of inorganic NMs focusing the particular requirement of the therapeutic ions needed for the targeted tissue types is further warranted. Equally important, while different types of inorganic NMs can first be synthesized and then be incorporated into nanofiber scaffolds, their distribution, appropriate content, and biocompatibility should be carefully considered. The inclusion of inappropriate amounts of inorganic components may lead to rapid release inducing cytotoxicity, which requires a careful attention. In addition, inorganic NPs need to be compounded with organic polymer materials for the preparation of electrospun nanofibers, and there are many limitations on the amount and size of doping, which need to be carefully considered for future applications during the fabrication of scaffolds. On the contrary, in-situ synthesis of inorganic NMs during electrospinning or their incorporation through reactive electrospinning based techniques may not only shorten the fabrication steps but may also afford advanced regenerative medicine and TE platforms. These approaches may further help develop off-the-shelf available nanofiber platforms for a range of injuries and defects.


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