Ultrasonic Generation of Pulsatile and Sequential Therapeutic Delivery Profiles from Calcium-Crosslinked Alginate Hydrogels

Abstract

Control over of biological processes can potentially be therapeutically regulated through localized biomolecular deliveries. While implantable hydrogels can provide localized therapeutic deliveries, they do not traditionally provide the temporally complex therapeutic delivery profiles required to regulate complex biological processes. Ionically crosslinked alginate hydrogels have been shown to release encapsulated payloads in response to a remotely applied ultrasonic stimulus, thus potentially enabling more temporally complex therapeutic delivery profiles. However, thorough characterizations of how different types of therapeutic payloads are retained and ultrasonically released need to be performed. Additionally, the impact of potentially disruptive ultrasonic stimulations on hydrogel structure and temperature need to be characterized to better understand what range of ultrasonic signals can be used to trigger release. To perform these characterizations, calcium-crosslinked alginate hydrogels were loaded with various model macromolecules (dextrans), chemotherapeutics, and protein signaling factors and exposed to a variety of single-pulse and multi-pulse ultrasonic signals at various amplitudes and durations. In response to single-pulsed ultrasonic exposures, quantifications of molecular release, degree of gel erosion, and increase in hydrogel temperature revealed that the ultrasonic stimulations required for statistically significant therapeutic deliveries often eroded and heated the gels to unacceptable levels. However, multi-pulse ultrasonic exposures were shown to achieve significant amounts of therapeutic release while keeping gel erosion and temperature increase at modest levels. Finally, experiments were performed demonstrating that ultrasonic stimulation could be used to generate drug release profiles shown to have potential therapeutic benefits (e.g., pulsatile and sequential anticancer delivery profiles). This work underscores the potential of using ultrasonically responsive polymeric hydrogels for providing on-demand control over more complex therapeutic deliver profiles and enhancing drug delivery strategies in cancer therapies and beyond.

Stimuli‐Responsive Biomaterials: Scaffolds for Stem Cell Control

“…Release of AuNP-BMP from hydrogel-microbeads D1 mMSCs Increased osteogenic (ALP) activity (from supernatant of stimulated material) [ 199] Fibrin hydrogels containing double emulsion particles (water-in-PFC-in-water) loaded with bFGF 5FU followed by irinotecan exposure reduced cell populations upon addition of free drug in plated culture [ 207] a) Non-stem cells.…”

“…Addressing this challenge, Emi and coauthors utilized a similar self-healing calcium-crosslinked alginate hydrogel system that allowed pulsatile payload release in response to ultrasound. [207] Individual payloads showing enhanced ultrasound-stimulated release included the signaling proteins VEGF and platelet derived growth factor (PDGF) as well as the chemotherapy agents irinotecan, mitoxantrone, and 5fluorouracil (5FU). Single ultrasound pulse exposures that resulted in drug release from the gels were often long enough in duration to also result in heating and gel erosion.…”

A Magnetically Responsive Hydrogel System for Controlling the Timing of Bone Progenitor Recruitment and Differentiation Factor Deliveries

“…This result is consistent with the previous literature showing that optimal frequencies of release are triggered at neither low (0.1 Hz) nor high (10 Hz) frequencies but rather frequencies in between (i.e., 1 Hz). 33,40 The BMP-2 release rate can be enhanced from biphasic ferrogel inner compartments by exposing them to continuous 1 Hz magnetic stimulation for 2 h (Figure 7A: red curve is higher than blue controls). Furthermore, if this enhancement in the BMP-2 release rate is desired in a delayed manner (i.e., triggered BMP-2 delivery on day 4), delayed application of the magnetic stimulation results in a delayed burst release of BMP-2 relative to controls (Figure 7Bi: red curve does not deviate from blue controls until magnetic stimulation starting at 96 h).…”

Recent Progress on Polysaccharide-Based Hydrogels for Controlled Delivery of Therapeutic Biomolecules

“… 51 Pulsatile release of the payloads could be successfully achieved by the application of a ultrasonic stimulus. 52 Ca 2+ cross-linked hydrogels can selectively release their payloads in response to this type of stimuli and self-heal when the stimuli stops due to Ca 2+ ion recross-linking the polymer network. 53 Therefore, this property enables an on-demand delivery of macromolecules such as GFs.…”

“…When implanted in a rodent model of sciatic nerve ligation and neurorrhaphy, these hydrogels were able to promote functional reinnervation . Pulsatile release of the payloads could be successfully achieved by the application of a ultrasonic stimulus . Ca 2+ cross-linked hydrogels can selectively release their payloads in response to this type of stimuli and self-heal when the stimuli stops due to Ca 2+ ion recross-linking the polymer network .…”