Date of Award
Doctor of Philosophy in Chemical Engineering
Samantha A. Meenach
Remotely activated hydrogel-based biomaterials can maximize the therapeutic effects by providing localized deliveries and minimizing off-target side effects. Smart hydrogels respond to an externally applied stimulus by delivering therapeutic molecules. While showing promise in releasing molecules in a precise spatial manner, they do not inherently provide temporally dynamic delivery profiles (e.g., controlled timing, rates, and sequences) required to direct sequences of biological events.
Biological processes are characterized by a sequence of events regulated by a complex interplay of signaling factors. For example, in the instance of ischemia (where a tissue no longer receives oxygen and nutrients due to a lack of blood perfusion), the establishment of new vascular networks in/out of the ischemic tissue is needed. To achieve this, angiogenic sprouts are instructed to emerge from existing nearby blood vessels through the presentation of proangiogenic signaling factors from the ischemic tissue. After entering into the ischemic tissue, angiogenic sprouts are instructed to become mature blood-perfusing vessels through localized presentations of pro-maturation signaling factors. In another coordinated biological process (i.e., the wound healing process), specific progenitor cells are recruited to the injury site where they must then be instructed to proliferate and differentiate into a robust population of tissue-specific cell types. Spatially, temporally, and sequentially coordinated presentation of cell-specific recruitment, proliferation, and differentiation factors are critical to the proper therapeutic outcome. Thus, in treatments that require proper wound healing and tissue re-vascularization, it is important to locally deliver therapeutics in spatiotemporally nuanced manners while hydrogels are well-suited for providing localized deliveries, traditional biomaterials not to provide the spatiotemporally nuanced delivery profiles needed to direct spatiotemporally complex biological processes, such as those that underly injuries and disease.
In addition to the regeneration of tissues and vascular networks in wound healing applications, cancer treatments can potentially be improved through spatiotemporally coordinated therapeutic deliveries. Localized deliveries of chemotherapeutics at tumor sites, for instance, can reduce off-target side-effects of toxic chemotherapeutics, and hydrogel-based materials are well-suited for providing these localized deliveries. However, the localized and sustained deliveries provided by polymeric hydrogels are not optimal for cancer treatments, especially regarding tumor cells’ abilities to develop resistance to chemotherapeutic agents when subjected to constant chemotherapeutic concentrations over protracted periods. Emerging cancer treatment strategies often employ temporally dynamic deliveries of single or multiple anticancer agents to prevent adaptive resistance and improve tumor regression.
In this dissertation, three types of polymeric hydrogel-based systems were developed - i) calcium crosslinked alginate hydrogels, ii) biphasic alginate ferrogels, iii) two-compartment hydrogel systems consisted of a gelatin outer compartment and ferrogel inner compartment. These hydrogel-based biomaterial systems were investigated to determine their potential for explicitly directing complex biological processes by providing temporally complex therapeutic delivery profiles. For instance, calcium-crosslinked hydrogels were subjected to short ultrasound pulsations (repeated on/off) to minimize hydrogel erosion and temperature increase while providing consistent and statistically significant chemotherapeutic release rates vs. time. Additionally, the sequential release of anticancer agents was demonstrated. Pulsatile mitoxantrone delivery profiles were also demonstrated from biphasic ferrogels when exposed to graded magnetic fields. Chemotherapeutic release rates could be explicitly controlled by stimulating at different magnetic field frequencies. Sequential release of protein signaling factors was also demonstrated by incorporating these magnetically responsive ferrogels into a compartmentalized hydrogel system. The outer gelatin compartment resulted in burst release of one cytokine (GM-CSF, VEGF, SDF-1α), whereas the inner ferrogel compartment provided on-demand, delayed the release of separate cytokines (HSP27, PDGF, BMP2) when subjected to magnetic stimulations. In both these ultrasonically and magnetically responsive gel systems, while hydrogels were stimulated by external energy fields, a safe region of operation was maintained. Ultrasound parameters (amplitude, frequency, duration, number of repeated pulses) were chosen such that gel heating does not exceed 450C temperature (80C above body temperature) critical for structural integrity of proteins and maintenance of biological homeostasis. The ferrogel-based systems required that only simple, benign, hand-held magnetics be used for stimulation and could be operated without thermally damaging tissues.
In summary, stimuli-responsive hydrogels systems were developed here, characterized, and demonstrated to provide a number of different therapeutic delivery profiles that are likely to have beneficial impacts on treatment strategies. These stimuli-responsive hydrogel-based biomaterials not only could generate these temporally complex deliveries, but they also could be triggered to produce these types of deliveries in an on-demand manner. This may be of particular clinical utility, in that clinicians will gain the flexibility to alter the course of therapies in real time, according to updates in patient prognosis. Finally, the hydrogel systems developed here will enable rapid optimization of complex delivery strategies in cancer treatments, wound healing, regenerative therapies, and in any treatment where control over complex biological processes is needed for improved therapeutic outcome.
Emi, Tania T., "REMOTELY ACTIVATED BIOMATERIALS FOR OPTIMIZING THE TEMPORAL PROFILES OF THERAPEUTIC MOLECULES" (2019). Open Access Dissertations. Paper 832.