Hydroxyapatite sonosensitization of ultrasound‐triggered, thermally responsive hydrogels: An on‐demand delivery system for bone repair applications

Abstract

While bones have the innate capability to physiologically regenerate, in certain cases regeneration is suboptimal, too slow, or does not occur. Biomaterials‐based growth factor delivery systems have shown potential for the treatment of challenging bone defects, however, achieving controlled growth factor release remains a challenge. The objective of this study was to develop a thermally responsive hydrogel for bone regeneration capable of ultrasound‐triggered on‐demand delivery of therapeutic agents. Furthermore, it was hypothesized that incorporation of hydroxyapatite (HA) into the hydrogel could increase sonosensitization, augmenting ultrasound sensitivity to enable controlled therapeutic release to the target tissue. Alginate thermally responsive P(Alg‐g‐NIPAAm) hydrogels were fabricated and varying quantities of HA (1, 3, 5, and 7% wt./vol.) incorporated. All hydrogels were highly injectable (maximum injection force below 6.5 N) and rheological characterization demonstrated their ability to gel at body temperature. The study demonstrated the ultrasound‐triggered release of sodium fluorescein (NaF), bovine serum albumin (BSA), and bone morphogenetic protein 2 (BMP‐2) from the hydrogels. Release rates of BSA and BMP‐2 were significantly enhanced in the HA containing hydrogels, confirming for the first time the role of HA as a son sensitizer. Together these results demonstrate the potential of these ultrasound‐triggered thermally responsive hydrogels for on‐demand delivery of therapeutic agents for bone regeneration.

Smart/stimuli-responsive hydrogels: Cutting-edge platforms for tissue engineering and other biomedical applications

“…Besides their great potential as tissue defects repair scaffolds [ 344 ]. Stimuli-responsive hydrogels have been consumed for reconstruction of different body tissues, including: cardiac tissue [ [345] , [346] , [347] ], neural tissue [ 335 , 334 ], skin [ [348] , [349] , [350] ], cornea [ 143 , [351] , [352] , [353] ], bone [ [354] , [355] , [356] ], cartilage [ [338] , [357] , [358] ], tendon [ 359 , 360 ], meniscus [ 361 ], and intervertebral disc [ 337 , 362 ]. Various smart/stimuli-responsive hydrogels employed for the engineering of different tissues are presented in Table 4 .…”

“…In the context of bone bioengineering, the employment of US stimuli as on-demand triggers during fracture healing and callus disruption is exceptionally appealing because of their additional valuable osteoinductive influence towards enhanced bone regeneration [ 17 ]. In a recent study, Levingstone and co-workers have designed temperature-responsive P(Alg-g-NIPAAm) hydrogels blended with hydroxyapatite (HAp) [ 354 ]. These hydrogels have presented great US triggered capacity for on-demand release of multiple bioactive therapeutics like sodium fluorescein (NaF), bovine serum albumin (BSA), and bone morphogenetic protein 2 (BMP-2) essential for osteo-regeneration.…”

Ultrasound-Induced Drug Release from Stimuli-Responsive Hydrogels

“…LIFU is advantageous for applications involving reversible cellular effects [ 15 ] and increased tissue regeneration [ 105 ]. For instance, Kearney et al [ 93 ] and Levingstone et al [ 106 ] used LIFU at 2.5 min per hour for 5 h with an intensity of 9.6 mW/cm 2 to induce bone regeneration aided by BMP-2 release. For applications involving irreversible cell death or tissue ablation, HIFU would most likely be preferred [ 107 ].…”

“…Tissue engineering hydrogel systems are rationally designed for a specific use, meaning each system has its own application, polymeric backbone, and delivery method ( Table 1 ). Some of the tissue engineering applications include bone regeneration [ 65 , 93 , 106 ], cartilage repair [ 72 , 115 ], and skin repair [ 116 ]. The polymeric backbone of responsive hydrogels includes materials such as alginate [ 93 , 106 ], chitosan [ 72 , 115 ], cellulose [ 116 ], fibrin [ 117 , 118 , 119 ], and collagen [ 65 ].…”

The Janus Nature of Nanohydroxyapatite in Tumor Progression

“…Hydroxyapatite (HAP; Ca 10 [PO 4 ] 6 [OH] 2 ) is the major inorganic constituent of the hard tissue of animals and humans. [ 22 ] Because of its excellent biocompatibility and bioactivity, synthetic HAP crystallites have now been used extensively and successfully as implants or coatings on implant prostheses. [ 23 ] Nanostructured materials generally offer improved performance over their larger particle‐sized counterparts because of their unique physicochemical properties.…”