Stimuli-Responsive Hydrogels for Local Post-Surgical Drug Delivery

Abstract

Currently, surgical operations, followed by systemic drug delivery, are the prevailing treatment modality for most diseases, including cancers and trauma-based injuries. Although effective to some extent, the side effects of surgery include inflammation, pain, a lower rate of tissue regeneration, disease recurrence, and the non-specific toxicity of chemotherapies, which remain significant clinical challenges. The localized delivery of therapeutics has recently emerged as an alternative to systemic therapy, which not only allows the delivery of higher doses of therapeutic agents to the surgical site, but also enables overcoming post-surgical complications, such as infections, inflammations, and pain. Due to the limitations of the current drug delivery systems, and an increasing clinical need for disease-specific drug release systems, hydrogels have attracted considerable interest, due to their unique properties, including a high capacity for drug loading, as well as a sustained release profile. Hydrogels can be used as local drug performance carriers as a means for diminishing the side effects of current systemic drug delivery methods and are suitable for the majority of surgery-based injuries. This work summarizes recent advances in hydrogel-based drug delivery systems (DDSs), including formulations such as implantable, injectable, and sprayable hydrogels, with a particular emphasis on stimuli-responsive materials. Moreover, clinical applications and future opportunities for this type of post-surgery treatment are also highlighted.

Keywords: drug delivery systems; hydrogel; implantable; injectable; sprayable.

Figure 1

(A) Schematic view of the application of the 3D-printed micro-robotic swimmers. Micro-swimmers are directed to the disease or intervention site using an external magnetic force. Tumor microenvironment pathological condition led to the enzymatic degradation of the micro-swimmer by matrix metalloproteinase-2 (MMP-2), and boosted labeled-magnetic nanoparticle release. Antibody-modified magnetic contrast agents diffuse around to label the untreated tissue sites, Reprinted with permission from American chemical society. Adapted with permission from Ceylan et al. [33]. (B) Illustration of the composition of fibrous bola-dipeptide hydrogels for localized and sustained delivery of prodrug towards the tumor site. Adapted with permission from Zou et al. [45]. (C) Poly (lactic-co-glycolic acid) (PLGA) microparticle loaded hyaluronan/methylcellulose (HAMC) hydrogel for local drug release to the stroke injured brain tissue. The exact location of the hydrogel is held in place by both gelation and a casing comprised of polycarbonate discs. Adapted with permission from Tuladhar et al. [49].

Figure 2

(A) Schematic illustration of injectable hydrogels in localized therapeutic agents’ delivery. It shows the required physical characteristics of the primary sol and as-injected gel for an ideal localized drug delivery depot. (B) Design and chemical composition of methacryloyl-substituted recombinant human tropoelastin (MeTro)/gelatin methacryloyl (GelMA)-AMP composite hydrogels. Schematic reaction of MeTro, GelMA, and AMP, after adding to TEA (co-initiator) and vinyl caprolactam (VC) (co-monomer) solutions. Eosin Y (photoinitiator) was finally introduced into the solution to become ready for spraying onto the wound area and exposing to visible light. Adapted with permission from Annabi et al. [69].

Figure 3

(A) (i) Camera photographs of BP@PLEL hydrogel sprayed on a piece of 37 °C artificial skin with (down) and without (up) 808 nm laser irradiation. Hydrogel membrane is formed in response to the near-infrared (NIR) laser. (ii) Schematic of the surgical treatment and postoperative photo-thermal therapy of the tumor at the site of the sprayed hydrogel. Adapted with permission from Shao et al. [71] (B) Illustration of the fabrication of sprayable system comprising hyaluronic acid (HA) hydrogel, crosslinked with SA-Ty mediated macromolecules (gelatin, HA_t), coupled with a neighboring amine, thiol, and another quinone. Adapted with permission from Kim et al. [72].

Figure 4

(A) Illustration of photo/chemo combination therapy via in situ formed thermal-sensitive polymer hydrogel (TNP) in a xenograft tumor model. Doxorubicin and zinc phthalocyanine loaded TNP polymer solution is transformed to gel state after injecting, to be used for localized photodynamic therapy. Adapted with permission from Huang et al. [77]; (B) relative tumor volume of the mice model in different treatment conditions showing the significance of concurrent localized chemo/PDT therapy. Adapted with permission from Huang et al. [77]. (C) Thermal fluctuations and corresponding on/off switch release of drug from thermo-responsive PIPAAm-PBMA micelles through the low critical solution temperature (LCST). Adapted with permission from Chung et al. [82]. (D) Hydrazide-functionalized poly N-isopropylacrylamide (PNIPAAm) microgels in a magnetic nanoparticle-containing matrix using for pulsatile on/off release of drugs in response to an external magnetic field. Adapted with permission from Campbell et al. [83]. (E) Ex vivo setup of the light-triggered release of the skin patch with drug reservoirs containing rhodamine-loaded hydrogel beads. It is shown that by the exposure of the visible light (LED lamp (30 mW·cm ⁻²) for 6 h), rhodamine is released from the Polydimethylsiloxane (PDMS)skin patch, which is significantly higher than that of “off “condition. Adapted with permission from Kim et al. [89].

Figure 5

(A) Schematic of reactive oxygen species (ROS)-sensitive drug delivery mechanism including ROS-mediated solubility change and ROS-mediated cleavage of hydrogels. Adapted with permission from Tu et al. [108]. (B) Schematic of pH-responsive swelling of anionic and cationic hydrogels in acidic and basic solutions.

Figure 6

(A) Illustration of the mechanisms of a hydrogel-forming adhesive microneedle patch consisting of a mussel adhesive protein-based swellable and sticky shell and a silk fibroin-based non-swellable core. It shows the structure and the reaction of the fabricated patches at the interface with the tissue. Adapted with permission from Jeon et al. [143]. (B) Synthesis illustration of the process for the formation of hyaluronic acid nanoparticle/miR-223*-laden GelMA hydrogels and the use of these adhesive hydrogels for wound healing. Adapted with permission from Gao et al. [144]. (C) Images of the wounds treated with Dulbecco’s phosphate-buffered saline (DPBS), GelMA, Neg miRNA incorporated GelMA, and miR-223* incorporated GelMAat days 0 and 12 of treatment. * Images for animals at day 12 were acquired after removal of the silicon splint to highlight the extent of wound healing. Adapted with permission from Saleh et al. [144].

Figure 7

(A) Spinal cord injury treatment using alginate hydrogel preparation encapsulated with multi-drug loaded PLGA particles for injection into the lesion site. Adapted with permission from Nazemi et al. [145]. (B) Localized administration of vortex-domain iron oxide-functionalized magnetic hydrogel for breast cancer postoperative recurrence prevention using its pH-responsivity. Adapted with permission from Gao et al. [148].