Harsha Ramaraju

Biodegradable shape memory polymers provide unique regenerative medicine approaches in minimally invasive surgeries. Once heated, thermally responsive shape memory polymer devices can be compressed, programmed to fit within a small profile, delivered in the cold programmed state, and expanded when heated to body temperature. We have previously developed a biodegradable shape memory elastomer (SME), poly(glycerol dodecanedioate) (PGD), with transition temperatures near 37°C exhibiting nonlinear elastic properties like numerous soft tissues. Using SMEs in the clinic requires disinfection and sterilization methods that conserve physiochemical, thermomechanical, and shape recovery properties. We evaluated disinfection protocols using 70% ethanol and UV254 nm for research applications and ethylene oxide (EtO) gas sterilization for clinical applications. Samples disinfected with ethanol for 0.5 and 1 min showed no changes in physiochemical material properties, but after 15 min showed slower recovery rates than controls (p < .05). EtO sterilization at 54.4°C decreased transition temperatures and shape recovery rate compared to EtO sterilization at 37.8°C (p < .01) and controls (p < .05). Aging samples for 9 months in a vacuum desiccator significantly reduced shape recovery, and the recovery rate in EtO sterilized samples compared to controls (p < .001). Cytotoxicity testing (ISO‐10993.5C:2012) revealed media extractions from EtO sterilized samples, sterilized at 37.8°C, and high‐density polyethylene negative control samples exhibit lower cytotoxicity (IC50) than Ethanol 1 min, UV 2 h, and EtO 54.4°C. Cell viability of NIH3T3 fibroblasts on sterilized surfaces was equivalent on EtO 37.7°C, EtO 54.4°C and Ethanol sterilized substrates. Finally, chromogenic bacterial endotoxin testing showed endotoxin levels were below the FDA prescribed levels for devices contacting blood and lymphatic tissues for ethanol 1 min, UV 120 min, EtO 37.7°C, EtO 54.4°C. These findings outline various disinfection and sterilization processes for research and pre‐clinical application and provide a pathway for developing custom sterilization cycles for the translation of biomedical devices utilizing PGD shape memory polymers.

This report describes the development of functionalized polymeric micelles encapsulating a chemotherapeutic agent. The results indicate the ability to achieve selective uptake into different cell populations in metastatic prostate cancer in vitro by appropriate selection of the targeting ligand. This paves the way for administering single or multiple therapeutic agents into bone metastases. These particles are functionalized to display the pVTK peptide of bisphosphonate (BP) as two different targeting ligands to assess their ability to trigger selective binding and internalization into prostate cancer cells, osteoblasts, osteoclasts, and macrophages in vitro. These bone-targeting particles (60-90 nm) bind to hydroxyapatite/bone powder with high affinity. Uptake of pVTK- and BP-conjugated particles into prostate cancer cells (PC-3 and C4-2B), MC3T3, RAW264.7 bone macrophages, and RANKL-activated RAW264.7 cells cultured on a regular tissue culture plate and bone-like surface was investigated. Results show that increasing the number of BP-targeting ligands displayed on particle surface shows 60-fold higher affinity to RAW 264.7 macrophages seeded on conventional tissue culture plates than non-conjugated particles. In addition, the uptake study results show that pVTK-functionalized particles were selectively internalized by C4-2B and MC3T3 osteoblast cells cultured on BLS, whereas BP-functionalized particles are selectively internalized by PC-3 and RAW264.7 macrophage cells cultured on BLS. Therefore, efficient and selective bone-conjugated therapies are needed to kill cancer cells and inhibit the crosstalk with other cells in the metastatic lesion, resulting in osteoblastic, osteolytic, or a mixed phenotype.

Shape memory materials, specifically nickel–titanium alloys, are used in a number of minimally invasive clinical procedures demonstrating significant improvements in clinical outcomes and standard of care compared to open procedures. However, concerns regarding erosion events, device failure, and consequent morbidities are driving interest in tissue engineering approaches which support or stimulate the patient's own tissue regenerative processes to repair and regenerate tissues. Growing interest in addressing these challenges using minimally invasive procedures is driving the rapid advancement of a new class of materials; biodegradable shape memory polymers (SMPs). These biodegradable SMPs are designed for compaction and delivery through keyhole incisions, expansion when they reach the target tissue, maintenance of mechanical continuity with surrounding tissues upon implantation, attachment of regenerative cells driving tissue growth and infiltration, and degradation into nontoxic byproducts. Polyesters are predominantly used in the design of these SMPs to impart biodegradability through hydrolysis. Use of homopolymers, copolymers, terpolymers, block‐copolymers, and interpenetrating networks has given rise to a range of SMPs spanning applications from endovascular to bone defect repair. Translating these materials to the clinic and applying these materials toward patient specific design can advance the current standard of care across various clinical disciplines.