Stretch‐Induced Drug Delivery from Superhydrophobic Polymer Composites: Use of Crack Propagation Failure Modes for Controlling Release Rates

Abstract

The concept of using crack propagation in polymeric materials to control drug release and its first demonstration are reported. The composite drug delivery system consists of highly-textured superhydrophobic electrosprayed microparticle coatings, composed of biodegradable and biocompatible polymers poly(caprolactone) and poly(glycerol monostearate carbonate-cocaprolactone), and a cellulose/polyester core. The release of entrapped agents is controlled by the magnitude of applied strain, resulting in a graded response from water infiltration through the propagating patterned cracks in the coating. Strain-dependent delivery of the anticancer agents cisplatin and 7-ethyl-10-hydroxycamptothecin to esophageal cancer cells (OE33) in vitro is observed. Finally the device is integrated with an esophageal stent to demonstrate delivery of fluorescein diacetate, using applied tension, to an ex vivo esophagus. Graphical AbstactDrug release is controlled by the magnitude of applied tensile strain through superhydrophobic composites. Strain-dependent in vitro delivery of anticancer agents (cisplatin and 7-ethyl-10-hydroxycamptothecin) to OE33 esophageal cancer cells and ex vivo delivery of fluorescein diacetate with esophageal stent integrated device are demonstrated. This system provides mechanoresponsive delivery for both hydrophilic and lipophilic compounds.Correspondence to: Mark W. Grinstaff.[ †] Authors have contributed equally to this work.Supporting information for this article is given via a link at the end of the document Mechanoresponsive polymeric materials are of significant interest as key functional elements in self-healing assemblies, [1] sensors and electronics, [2] and biology/medicine. [3] Consequently, mechanoresponsive materials are actively being developed that respond to mechanical stimuli such as compression, [4] tension, [5] shear, [6] or ultrasound. [7] Implanted medical devices also experience many of these forces, and even exert their own mechanical forces during use (e.g., stents). [8] Our approach to designing functional mechanoresponsive materials for drug delivery uses crack propagation failure modes of composite materials to control drug release. We hypothesized that crack formation could be initiated and propagated through superhydrophobic coatings on a multilayered drug delivery system by applying tension, with consequent device wetting and drug release. Given our interests in triggered drug release from polymeric [9] and superhydrophobic [10] materials, we realized an opportunity to design and evaluate such a new drug delivery system for an esophageal stent. Herein, we report: (1) the fabrication of a multilayered electrosprayed polymeric device; (2) the entrapment and subsequent controlled release of both hydrophilic and lipophilic agents under various applied strains; (3) analysis of the crack propagation mechanism with determination of the fracture toughness and critical strain energy release rate; (4) the demonstration of in vitro tension-mediated delivery of cisplatin...

Superhydrophobic materials for biomedical applications

“…Finally, Wang and Kaplan, et al explored the use of superhydrophobic, electrosprayed coatings as a mechano-responsive drug delivery system where release of either a hydrophilic or a hydrophobic drug is controlled by the amount of applied strain. In this system, the drug loaded core is sandwiched between two superhydrophobic, electrosprayed coatings, and the applied mechanical force induced cracks in the coating with subsequent release of the drugs [222]. …”

Mechanoresponsive materials for drug delivery: Harnessing forces for controlled release

“…Developing a superhydrophobic system for drug delivery, Wang and Kaplan et al control drug release based on tensile strain and further integrate their system with an esophageal stent for ex vivo delivery [141]. In the absence of tensile strain, the superhydrophobic coating, an electrosprayed mixture of biocompatible, biodegradable low surface energy polymers poly(ε-caprolactone) and poly(glycerol monstearate carbonate- co -caprolactone), impedes water infiltration into the hydrophilic drug core (composed of cellulose/polyester), in contrast to a hydrophobic coating of poly(ε-caprolactone) (contact angle = 119°) (Figure 8e).…”

“…These systems possess: 1) the mechanical strength to be subjected to high tensile strains, 2) capsular or layered composites to encapsulate drugs and proteins, and 3) cycle- or strain-dependent release. Since the first report in 1997, only one delivery system out of nine has evaluated performance in vivo (stretched microneedles containing insulin microparticles prolong delivery in diabetic mice [123]) and only one other delivery system has evaluated performance ex vivo (drug release from a superhydrophobic composite is triggered by the expansion of the device, integrated with an esophageal stent, in ex vivo bovine esophagus [141]).…”

“…Treatment can also be enhanced by integrating mechanoresponsive drug or protein delivery systems with existing mechanical medical devices, such as stents and catheters. The radial expansion of esophageal stents, which treat esophageal cancer, acts as a trigger to control delivery of chemotherapeutics [141]. Other systems offer new mechanical approaches to treatment; user-controlled delivery of drugs and proteins are reported for pain management, neoangiogenesis, and diabetes.…”

“…For example, there are no examples of nucleic acids being delivered by such systems, and delivery of only one type of growth factor (VEGF [103]), one type of antibody (anti-TNFα [152]), three proteins/ enzymes (insulin [99,123], glucose oxidase [145], tissue plasminogen activator [147,148]), one polysaccharide (heparin [149]), and seven small molecules (ondansetron [106], hydrocortisone [107], dexamethasone [108], doxorubicin [123], paclitaxel [133], cisplatin [141], and camptothecin [141]) have been described. Delivery is further complicated by the necessity to preserve the activity of small molecules and proteins within the mechanoreponsive systems.…”