Chemical Modifications of Porous Shape Memory Polymers for Enhanced X-ray and MRI Visibility.

The goal of this work was to develop a shape memory polymer (SMP) foam with visibility under both X-ray and magnetic resonance imaging (MRI) modalities. A porous polymeric material with these properties is desirable in medical device development for applications requiring thermoresponsive tissue scaffolds with clinical imaging capabilities. Dual modality visibility was achieved by chemically incorporating monomers with X-ray visible iodine-motifs and MRI visible monomers with gadolinium content. Physical and thermomechanical characterization showed the effect of increased gadopentetic acid (GPA) on shape memory behavior. Multiple compositions showed brightening effects in pilot, T1-weighted MR imaging. There was a correlation between the polymeric density and X-ray visibility on expanded and compressed SMP foams. Additionally, extractions and indirect cytocompatibility studies were performed to address toxicity concerns of gadolinium-based contrast agents (GBCAs). This material platform has the potential to be used in a variety of medical devices.

Injectable PolyMIPE Scaffolds for Soft Tissue Regeneration.

Injury caused by trauma, burns, surgery, or disease often results in soft tissue loss leading to impaired function and permanent disfiguration. Tissue engineering aims to overcome the lack of viable donor tissue by fabricating synthetic scaffolds with the requisite properties and bioactive cues to regenerate these tissues. Biomaterial scaffolds designed to match soft tissue modulus and strength should also retain the elastomeric and fatigue-resistant properties of the tissue. Of particular design importance is the interconnected porous structure of the scaffold needed to support tissue growth by facilitating mass transport. Adequate mass transport is especially true for newly implanted scaffolds that lack vasculature to provide nutrient flux. Common scaffold fabrication strategies often utilize toxic solvents and high temperatures or pressures to achieve the desired porosity. In this study, a polymerized medium internal phase emulsion (polyMIPE) is used to generate an injectable graft that cures to a porous foam at body temperature without toxic solvents. These poly(ester urethane urea) scaffolds possess elastomeric properties with tunable compressive moduli (20-200 kPa) and strengths (4-60 kPa) as well as high recovery after the first conditioning cycle (97-99%). The resultant pore architecture was highly interconnected with large voids (0.5-2 mm) from carbon dioxide generation surrounded by water-templated pores (50-300 µm). The ability to modulate both scaffold pore architecture and mechanical properties by altering emulsion chemistry was demonstrated. Permeability and form factor were experimentally measured to determine the effects of polyMIPE composition on pore interconnectivity. Finally, initial human mesenchymal stem cell (hMSC) cytocompatibility testing supported the use of these candidate scaffolds in regenerative applications. Overall, these injectable polyMIPE foams show strong promise as a biomaterial scaffold for soft tissue repair.

Fabrication and In Vivo Assessment of Oxidatively Responsive PolyHIPE Scaffolds for Use in Diabetic Orthopedic Applications.

Achieving surgical success in orthopedic patients with metabolic disease remains a substantial challenge. Diabetic patients exhibit a unique tissue microenvironment consisting of high levels of reactive oxygen species (ROS), which promotes osteoclastic activity and leads to decreased bone healing. Alternative solutions, such as synthetic grafts, incorporating progenitor cells or growth factors, can be costly and have processing constraints. Previously, the potential for thiol-methacrylate networks to sequester ROS while possessing tunable mechanical properties and degradation rates has been demonstrated. In this study, the ability to fabricate thiol-methacrylate interconnected porous scaffolds using emulsion templating to create monoliths with an average porosity of 97.0% is reported. The average pore sizes of the scaffolds range from 27 to 656 µm. The scaffolds can sequester pathologic levels of ROS via hydrogen peroxide consumption and are not impacted by sterilization. Subcutaneous implantation shows no signs of acute toxicity. Finally, in a 6-week bilateral calvarial defect model in Zucker diabetic fatty rats, ROS scaffolds increase new bone volume by 66% over sham defects. Histologic analysis identifies woven bone infiltration throughout the scaffold and neovascularization. Overall, this study suggests that porous thiol-methacrylate scaffolds may improve healing for bone grafting applications where high levels of ROS hinder bone growth.

Technical note: The design and validation of a multi-modality lung phantom.

BACKGROUND: Clinically relevant models that enable certain tasks such as calibration of medical imaging devices or techniques, device validation, training healthcare professionals, and more are vital to research throughout the medical field and are referred to as phantoms. Phantoms range in complexity from a vile of water to complex designs that emulate in vivo properties. PURPOSE: Specific phantoms that model the lungs have focused on replication of tissue properties but lack replication of the anatomy. This limits the use across multiple imaging modalities and for device testing when anatomical considerations as well as tissue properties are needed. This work reports a lung phantom design utilizing materials that accurately mimic the ultrasound and magnetic resonance imaging (MRI) properties of in vivo lungs and includes relevant anatomical equivalence. METHODS: The tissue mimicking materials were selected based on published studies of the materials, through qualitative comparisons of the materials with ultrasound imaging, and quantitative MRI relaxation values. A PVC ribcage was used as the structural support. The muscle/fat combined layer and the skin layer were constructed with various types of silicone with graphite powder added as a scattering agent where appropriate. Lung tissue was mimicked with silicone foam. The pleural layer was replicated by the interface between the muscle/fat layer and the lung tissue layer, requiring no additional material. RESULTS: The design was validated by accurately mimicking the distinct tissue layers expected with in vivo lung ultrasound while maintaining tissue-mimicking relaxation values in MRI as compared to reported values. Comparisons between the muscle/fat material and in vivo muscle/fat tissue demonstrated a 1.9% difference in T1 relaxation and a 19.8% difference in T2 relaxation. CONCLUSIONS: Qualitative US and quantitative MRI analysis verified the proposed lung phantom design for accurate modeling of the human lungs.

Development of Biopsy Tract Sealants Based on Shape Memory Polymer Foams.

Lung biopsies are often used to aid in the diagnosis of cancers. However, the procedure carries the dual risk of air (pneumothorax) or blood (hemothorax) filling the pleural cavity, increasing the risk of a collapsed lung and chest intubation. This work demonstrates the effectiveness of a polyurethane-based shape memory polymer foam as a biopsy tract sealant. The impact of diameter, length, pore size, and shape memory effect was evaluated to determine the ideal device design for tract sealing. Characterization in an in vitro benchtop lung model identified that diameter had the largest influence on sealing efficacy, while the length of the device had little to no impact. Finally, evaluation of deployment force demonstrated that devices fabricated from the shape memory polymer foams were easier to deploy than elastic foams. Following characterization, down-selected device designs were combined with radiopaque markers for use in image-guided based procedures. Furthermore, the introduction of the markers or sterilization did not impact the ability of the devices to seal the biopsy tract and led to a decrease in the deployment force. Overall, these results demonstrate the potential for polyurethane-based shape memory foam devices to serve as biopsy tract sealant devices that aim to reduce complications, such as pneumothorax, from occurring.

Swellable and Thermally Responsive Hydrogel/Shape Memory Polymer Foam Composites for Sealing Lung Biopsy Tracts.

Lung tissue biopsies can result in a leakage of blood (hemothorax) and air (pneumothorax) from the biopsy tract, which threatens the patient with a collapsed lung and other complications. We have developed a lung biopsy tract sealant based on a thiol-ene-crosslinked PEG hydrogel and polyurethane shape memory polymer (SMP) foam composite. After insertion into biopsy tracts, the PEG hydrogel component contributes to sealing through water-driven swelling, whereas the SMP foam contributes to sealing via thermal actuation. The gelation kinetics, swelling properties, and rheological properties of various hydrogel formulations were studied to determine the optimal formulation for composite fabrication. Composites were then fabricated via vacuum infiltration of the PEG hydrogel precursors into the SMP foam followed by thermal curing. After drying, the composites were crimped to enable insertion into biopsy tracts. Characterization revealed that the composites exhibited a slight delay in shape recovery compared to control SMP foams. However, the composites were still able to recover their shape in a matter of minutes. Cytocompatibility testing showed that leachable byproducts can be easily removed by washing and washed composites were not cytotoxic to mouse lung fibroblasts (L929s). Benchtop testing demonstrated that the composites can be easily deployed through a cannula, and the working time for deployment after exposure to water was 2 min. Furthermore, testing in an in vitro lung model demonstrated that the composites were able to effectively seal a lung biopsy tract and prevent air leakage. Collectively, these results show that the PEG hydrogel/SMP foam composites have the potential to be used as lung biopsy tract sealants to prevent pneumothorax post-lung biopsy.

Development and Characterization of Oxidatively Responsive Thiol-Ene Networks for Bone Graft Applications.

First metatarsophalangeal joint (MPJ) arthroplasty procedures are a common podiatric procedure. However, almost one-third of cases require revision surgeries because of nonunions. Revision or salvage surgery requires more extensive hardware and bone grafts to recreate the first metatarsal. Unfortunately, salvage surgeries have a similar rate of failure attributed to delayed healing, bone graft dissolution, and the lack of bone ingrowth. Furthermore, patients who suffer from neuropathic comorbidities such as diabetes suffer from a diminished healing capacity. An increase in proinflammatory factors and the high presence of reactive oxygen species (ROS) present in diabetics are linked to lower fusion rates. To this end, there is a need for a clinically relevant bone graft to promote bone fusions in patients with neuropathic comorbidities. Incorporating thiol-ene networks for bone scaffolds has demonstrated increased osteogenic biomarkers over traditional polymeric materials. Furthermore, thiol-ene networks can act as antioxidants. Sulfide linkages within the network have an inherent ability to consume radical oxygen to create sulfoxide and sulfone groups. These unique properties of thiol-ene networks make them a promising candidate as bone grafts for diabetic patients. In this work, we propose a thiol-ene biomaterial to address the current limitations of MPJ fusion in diabetics by characterizing mechanical properties, degradation rates under accelerated conditions, and oxidative responsiveness under pathophysiologic conditions. We also demonstrated that thiol-ene-based materials could reduce the number of hydroxyl radicals associated with neuropathic comorbidities.

Controlling Morphology and Physio-Chemical Properties of Stimulus-Responsive Polyurethane Foams by Altering Chemical Blowing Agent Content.

Amorphous shape memory polymer foams are currently used as components in vascular occlusion medical devices such as the IMPEDE and IMPEDE-FX Embolization Plugs. Body temperature and moisture-driven actuation of the polymeric foam is necessary for vessel occlusion and the rate of expansion is a function of physio-chemical material properties. In this study, concentrations of the chemical blowing agent for the foam were altered and the resulting effects on morphology, thermal and chemical properties, and actuation rates were studied. Lower concentration of chemical blowing agent yielded foams with thick foam struts due to less bubble formation during the foaming process. Foams with thicker struts also had high tensile modulus and lower strain at break values compared to the foams made with higher blowing agent concentration. Additionally, less blowing agent resulted in foams with a lower glass transition temperature due to less urea formation during the foaming reaction. This exploratory study provides an approach to control thermo-mechanical foam properties and morphology by tuning concentrations of a foaming additive. This work aims to broaden the applications of shape memory polymer foams for medical use.

Comparison of clinical explants and accelerated hydrolytic aging to improve biostability assessment of silicone-based polyurethanes.

Although silicone-based polyurethanes have demonstrated increased oxidative stability, there have been conflicting reports of the long-term hydrolytic stability of Optim™ and PurSil(®) 35 based on recent temperature-accelerated hydrolysis studies. The goal of the current study was to identify in vitro-in vivo correlations to determine the relevance of this accelerated in vitro model for predicting clinical outcomes. Temperature-accelerated hydrolytic aging of three commonly used cardiac lead insulation materials, Optim™, Elasthane™ 55D, Elasthane™ 80A, and a related silicone-polyurethane, PurSil(®) 35, was performed. After 1 year at 85°C, similar losses in Mn and Mz were observed for the poly(ether urethanes), but an increase in Mz loss as compared to Mn loss was observed for the silicone-based polyurethanes. A similar trend of increased Mz loss as compared to Mn loss was observed in explanted Optim™ leads after 2-3 years; however, no statistically significant Mn loss was detected between 2-3 and 7-8 years of implantation. Given this preferential loss of high molecular weight chains, it was hypothesized that the observed differences between the polyurethanes were due to allophanate dissociation rather than backbone chain scission. Following full dissociation of the small percentage of allophanates in vivo, the observed molecular weight stability and proven clinical performance of Optim™ was attributed to the well-documented stability of the urethane bond under physiological conditions. This allophanate dissociation reaction is incompatible with the first order mechanism proposed in previous temperature-accelerated hydrolysis studies and may be the reason for the model's inaccurate prediction of significant and progressive molecular weight loss in vivo. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1805-1816, 2016.

Chronic Wound Dressings Based on Collagen-Mimetic Proteins.

Objective: Chronic wounds are projected to reach epidemic proportions due to the aging population and the increasing incidence of diabetes. There is a strong clinical need for an improved wound dressing that can balance wound moisture, promote cell migration and proliferation, and degrade at an appropriate rate to minimize the need for dressing changes. Approach: To this end, we have developed a bioactive, hydrogel microsphere wound dressing that incorporates a collagen-mimetic protein, Scl2GFPGER, to promote active wound healing. A redesigned Scl2GFPGER, engineered collagen (eColGFPGER), was created to reduce steric hindrance of integrin-binding motifs and increase overall stability of the triple helical backbone, thereby resulting in increased cell adhesion to substrates. Results: This study demonstrates the successful modification of the Scl2GFPGER protein to eColGFPGER, which displayed enhanced stability and integrin interactions. Fabrication of hydrogel microspheres provided a matrix with adaptive moisture technology, and degradation rates have potential for use in human wounds. Innovation: This collagen-mimetic wound dressing was designed to permit controlled modulation of cellular interactions and degradation rate without impact on other physical properties. Its fabrication into uniform hydrogel microspheres provides a bioactive dressing that can readily conform to irregular wounds. Conclusion: Overall, this new eColGFPGER shows strong promise in the generation of bioactive hydrogels for wound healing as well as a variety of tissue scaffolds.

Limitations of predicting in vivo biostability of multiphase polyurethane elastomers using temperature-accelerated degradation testing.

Polyurethane biostability has been the subject of intense research since the failure of polyether polyurethane pacemaker leads in the 1980s. Accelerated in vitro testing has been used to isolate degradation mechanisms and predict clinical performance of biomaterials. However, validation that in vitro methods reproduce in vivo degradation is critical to the selection of appropriate tests. High temperature has been proposed as a method to accelerate degradation. However, correlation of such data to in vivo performance is poor for polyurethanes due to the impact of temperature on microstructure. In this study, we characterize the lack of correlation between hydrolytic degradation predicted using a high temperature aging model of a polydimethylsiloxane-based polyurethane and its in vivo performance. Most notably, the predicted molecular weight and tensile property changes from the accelerated aging study did not correlate with clinical explants subjected to human biological stresses in real time through 5 years. Further, DMTA, ATR-FTIR, and SAXS experiments on samples aged for 2 weeks in PBS indicated greater phase separation in samples aged at 85°C compared to those aged at 37°C and unaged controls. These results confirm that microstructural changes occur at high temperatures that do not occur at in vivo temperatures. In addition, water absorption studies demonstrated that water saturation levels increased significantly with temperature. This study highlights that the multiphase morphology of polyurethane precludes the use of temperature accelerated biodegradation for the prediction of clinical performance and provides critical information in designing appropriate in vitro tests for this class of materials.

Synthesis of collagenase-sensitive polyureas for ligament tissue engineering.

Recently, poly(ester urethanes) were investigated for use as ligament grafts due to their exceptional mechanical properties and highly tunable structure; however, these grafts are susceptible to hydrolytic degradation that occurs independent of tissue regeneration. To address this limitation, polyureas containing collagen-derived peptides were synthesized which enable cellular release of proteases to dictate degradation rate. It is hypothesized that this cell-responsive design will facilitate load transfer from the biodegradable scaffold to neotissue at a rate that promotes proper tissue orientation and function while maintaining construct integrity.