Photothermal and Immunomodulatory Nanomaterials for Tissue Repair

Sutures, staples and tissue glues remain the primary means of tissue approximation and vessel ligation. Despite widespread use, conventional sutures do not immediately seal approximated tissue and are susceptible to bacterial leakage, wound re-opening and infection. Laser-activated tissue sealing is an alternative approach which conventionally employs light-absorbing chromophores and nanoparticles for converting near infrared (NIR) laser to heat. The local increase in temperature engenders interdigitation of sealant and tissue biomolecules, resulting in rapid tissue sealing. We developed laser-activated nanosealants (LANS) in which, gold nanorods (GNRs) or indocyanine green (ICG) dye are embedded within a biopolymer matrix (collagen, silk or elastin-like polypeptides). We also fabricated novel laser-activated tissue-integrating sutures (LATIS) that synergize the benefits of conventional suturing and laser sealing. These laser-activated approximation devices demonstrated higher efficacies for tissue biomechanical recovery and repair in a full-thickness, dorsal surgical incision model in immunocompetent mice compared to commercial sutures and cyanoacrylate skin glue. Localized delivery of modulators of tissue repair, including histamine and copper, further improved healed skin strength following laser sealing and application. LANS films loaded with antibacterial drugs were able to significantly lower MRSA loads at the wound compared to antibacterial sutures, indicating a multifunctional strategy that synergizes rapid sealing with combating surgical site infections. In addition to incisional wounds, histamine co-delivered with silk LANS films accelerated the closure of full thickness, splinted excisional wounds in immunocompetent BALB/c mice and genetically obese and diabetic db/db mice, resulting in faster closure than Tegaderm wound dressing. Histological and immunohistochemistry analyses showed LANS-histamine treatment reduced dermal gap, promoted angiogenesis (CD31+), myofibroblast-mediated wound contraction (aSMA+), and higher TGF-β1 expression which are hallmarks of improved healing outcomes. Growth factor proteins have been investigated in tissue repair but have demonstrated limited efficacies as monotherapies. In order to address this, we first generated and characterized fusion polypeptide growth factor nanoparticles (GFNPs) that demonstrated high stabilities in wound fluid. Combination treatments of LANS-histamine and GFNPs resulted in higher efficacies of wound closure and tissue repair compared to monotherapies acting alone. An investigation into the kinetics of wound closure indicated that temporally sequential delivery of LANS-histamine followed by GFNPs, coinciding with different stages of tissue repair, demonstrated the highest efficacies of wound closure and tissue repair. Our results indicate that laser sealing and approximation, together with delivery of immunomodulatory mediators, can lead to faster healing and tissue repair, thus reducing wound dehiscence, preventing wounds moving towards chronicity and lowering incidence of surgical site infections, all of which can have significant impact in the clinic.