Effect of pore size and spacing on neovascularization of a biodegradble shape memory polymer perivascular wrap.

Neointimal hyperplasia (NH) is a main source of failures in arteriovenous fistulas and vascular grafts. Several studies have demonstrated the promise of perivascular wraps to reduce NH via promotion of adventitial neovascularization and providing mechanical support. Limited clinical success thus far may be due to inappropriate material selection (e.g., nondegradable, too stiff) and geometric design (e.g., pore size and spacing, diameter). The influence of pore size and spacing on implant neovascularization is investigated here for a new biodegradable, thermoresponsive shape memory polymer (SMP) perivascular wrap. Following an initial pilot, 21 mice were each implanted with six scaffolds: four candidate SMP macroporous designs (a-d), a nonporous SMP control (e), and microporous GORETEX (f). Mice were sacrificed after 4 (N = 5), 14 (N = 8), and 28 (N = 8) days. There was a statistically significant increase in neovascularization score between all macroporous groups compared to nonporous SMP (p < .023) and microporous GORETEX (p < .007) controls at Day 28. Wider-spaced, smaller-sized pore designs (223 µm-spaced, 640 µm-diameter Design c) induced the most robust angiogenic response, with greater microvessel number (p < .0114) and area (p < .0055) than nonporous SMPs and GORETEX at Day 28. This design also produced significantly greater microvessel density than nonporous SMPs (p = 0.0028) and a smaller-spaced, larger-sized pore (155 µm-spaced, 1,180 µm-sized Design b) design (p = .0013). Strong neovascularization is expected to reduce NH, motivating further investigation of this SMP wrap with controlled pore spacing and size in more advanced arteriovenous models.

Recent strategies to design vascular theranostic nanoparticles.

Vascular disease is a leading cause of death and disability worldwide. Current surgical intervention and treatment options for vascular diseases have exhibited limited long-term success, emphasizing the need to develop advanced treatment paradigms for early detection and more effective treatment of dysfunctional cells in a specific blood vessel lesion. Advances in targeted nanoparticles mediating cargo delivery enables more robust prevention, screening, diagnosis, and treatment of vascular disorders. In particular, nanotheranostics integrates diagnostic imaging and therapeutic function into a single agent, and is an emerging platform towards more effective and localized vascular treatment. This review article highlights recent advances and current challenges associated with the utilization of targeted nanoparticles for real-time diagnosis and treatment of vascular diseases. Given recent developments, nanotheranostics offers great potential to serve as an effective platform for targeted, localized, and personalized vascular treatment.

Tunable Surface Repellency Maintains Stemness and Redox Capacity of Human Mesenchymal Stem Cells.

Human bone marrow derived mesenchymal stem cells (hMSCs) hold great promise for regenerative medicine due to their multipotent differentiation capacity and immunomodulatory capabilities. Substantial research has elucidated mechanisms by which extracellular cues regulate hMSC fate decisions, but considerably less work has addressed how material properties can be leveraged to maintain undifferentiated stem cells. Here, we show that synthetic culture substrates designed to exhibit moderate cell-repellency promote high stemness and low oxidative stress-two indicators of naïve, healthy stem cells-in commercial and patient-derived hMSCs. Furthermore, the material-mediated effect on cell behavior can be tuned by altering the molar percentage (mol %) and/or chain length of poly(ethylene glycol) (PEG), the repellant block linked to hydrophobic poly(ε-caprolactone) (PCL) in the copolymer backbone. Nano- and angstrom-scale characterization of the cell-material interface reveals that PEG interrupts the adhesive PCL domains in a chain-length-dependent manner; this prevents hMSCs from forming mature focal adhesions and subsequently promotes cell-cell adhesions that require connexin-43. This study is the first to demonstrate that intrinsic properties of synthetic materials can be tuned to regulate the stemness and redox capacity of hMSCs and provides new insight for designing highly scalable, programmable culture platforms for clinical translation.

Copolymer-Mediated Cell Aggregation Promotes a Proangiogenic Stem Cell Phenotype In Vitro and In Vivo.

Material-induced cell aggregation drives a proangiogenic expression profile. Copolymer substrates containing cell-repellent and cell-adhesive domains force the aggregation of human mesenchymal stem cells, which results in enhanced tubulogenesis in vitro and stabilization of vasculature in vivo. These findings can be used to design instructive biomaterial scaffolds for clinical use.

Biomaterial-Based Approaches to Address Vein Graft and Hemodialysis Access Failures.

Veins used as grafts in heart bypass or as access points in hemodialysis exhibit high failure rates, thereby causing significant morbidity and mortality for patients. Interventional or revisional surgeries required to correct these failures have been met with limited success and exorbitant costs, particularly for the US Centers for Medicare & Medicaid Services. Vein stenosis or occlusion leading to failure is primarily the result of neointimal hyperplasia. Systemic therapies have achieved little long-term success, indicating the need for more localized, sustained, biomaterial-based solutions. Numerous studies have demonstrated the ability of external stents to reduce neointimal hyperplasia. However, successful results from animal models have failed to translate to the clinic thus far, and no external stent is currently approved for use in the US to prevent vein graft or hemodialysis access failures. This review discusses current progress in the field, design considerations, and future perspectives for biomaterial-based external stents. More comparative studies iteratively modulating biomaterial and biomaterial-drug approaches are critical in addressing mechanistic knowledge gaps associated with external stent application to the arteriovenous environment. Addressing these gaps will ultimately lead to more viable solutions that prevent vein graft and hemodialysis access failures.

Noncovalent Pi-Pi Stacking at the Carbon-Electrolyte Interface: Controlling the Voltage Window of Electrochemical Supercapacitors.

A key parameter in the operation of an electrochemical double-layer capacitor is the voltage window, which dictates the device energy density and power density. Here we demonstrate experimental evidence that π-π stacking at a carbon-ionic liquid interface can modify the operation voltage of a supercapacitor device by up to 30%, and this can be recovered by steric hindrance at the electrode-electrolyte interface introduced by poly(ethylene oxide) polymer electrolyte additives. This observation is supported by Raman spectroscopy, electrochemical impedance spectroscopy, and differential scanning calorimetry that each independently elucidates the signature of π-π stacking between imidazole groups in the ionic liquid and the carbon surface and the role this plays to lower the energy barrier for charge transfer at the electrode-electrolyte interface. This effect is further observed universally across two separate ionic liquid electrolyte systems and is validated by control experiments showing an invariant electrochemical window in the absence of a carbon-ionic liquid electrode-electrolyte interface. As interfacial or noncovalent interactions are usually neglected in the mechanistic picture of double-layer capacitors, this work highlights the importance of understanding chemical properties at supercapacitor interfaces to engineer voltage and energy capability.

Reprint of: Pendant allyl crosslinking as a tunable shape memory actuator for vascular applications.

Thermo-responsive shape memory polymers (SMPs) can be programmed to fit into small-bore incisions and recover their functional shape upon deployment in the body. This property is of significant interest for developing the next generation of minimally-invasive medical devices. To be used in such applications, SMPs should exhibit adequate mechanical strengths that minimize adverse compliance mismatch-induced host responses (e.g. thrombosis, hyperplasia), be biodegradable, and demonstrate switch-like shape recovery near body temperature with favorable biocompatibility. Combinatorial approaches are essential in optimizing SMP material properties for a particular application. In this study, a new class of thermo-responsive SMPs with pendant, photocrosslinkable allyl groups, x%poly(ε-caprolactone)-co-y%(α-allyl carboxylate ε-caprolactone) (x%PCL-y%ACPCL), are created in a robust, facile manner with readily tunable material properties. Thermomechanical and shape memory properties can be drastically altered through subtle changes in allyl composition. Molecular weight and gel content can also be altered in this combinatorial format to fine-tune material properties. Materials exhibit highly elastic, switch-like shape recovery near 37 °C. Endothelial compatibility is comparable to tissue culture polystyrene (TCPS) and 100%PCL in vitro and vascular compatibility is demonstrated in vivo in a murine model of hindlimb ischemia, indicating promising suitability for vascular applications. STATEMENT OF SIGNIFICANCE: With the ongoing thrust to make surgeries minimally-invasive, it is prudent to develop new biomaterials that are highly compatible and effective in this workflow. Thermo-responsive shape memory polymers (SMPs) have great potential for minimally-invasive applications because SMP medical devices (e.g. stents, grafts) can fit into small-bore minimally-invasive surgical devices and recover their functional shape when deployed in the body. To realize their potential, it is imperative to devise combinatorial approaches that enable optimization of mechanical, SM, and cellular responses for a particular application. In this study, a new class of thermo-responsive SMPs is created in a robust, facile manner with readily tunable material properties. Materials exhibit excellent, switch-like shape recovery near body temperature and promising biocompatibility for minimally-invasive vascular applications.

Differential responses of induced pluripotent stem cell-derived cardiomyocytes to anisotropic strain depends on disease status.

Primary dilated cardiomyopathy (DCM) is a non-ischemic heart disease with impaired pumping function of the heart. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a healthy volunteer and a primary DCM patient to investigate the impact of DCM on iPSC-CMs׳ responses to different types of anisotropic strain. A bioreactor system was established that generates cardiac-mimetic forces of 150 kPa at 5% anisotropic cyclic strain and 1 Hz frequency. After confirming cardiac induction of the iPSCs, it was determined that fibronectin was favorable to other extracellular matrix protein coatings (gelatin, laminin, vitronectin) in terms of viable cell area and density, and was therefore selected as the coating for further study. When iPSC-CMs were exposed to three strain conditions (no strain, 5% static strain, and 5% cyclic strain), the static strain elicited significant induction of sarcomere components in comparison to other strain conditions. However, this induction occurred only in iPSC-CMs from a healthy volunteer ("control iPSC-CMs"), not in iPSC-CMs from the DCM patient ("DCM iPSC-CMs"). The donor type also significantly influenced gene expressions of cell-cell and cell-matrix interaction markers in response to the strain conditions. Gene expression of connexin-43 (cell-cell interaction) had a higher fold change in healthy versus diseased iPSC-CMs under static and cyclic strain, as opposed to integrins α-5 and α-10 (cell-matrix interaction). In summary, our iPSC-CM-based study to model the effects of different strain conditions suggests that intrinsic, genetic-based differences in the cardiomyocyte responses to strain may influence disease manifestation in vivo.

Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes.

Cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) hold great promise for modeling human heart diseases. However, iPSC-CMs studied to date resemble immature embryonic myocytes and therefore do not adequately recapitulate native adult cardiomyocyte phenotypes. Since extracellular matrix plays an essential role in heart development and maturation in vivo, we sought to develop a synthetic culture matrix that could enhance functional maturation of iPSC-CMs in vitro. In this study, we employed a library of combinatorial polymers comprising of three functional subunits - poly-ε-caprolacton (PCL), polyethylene glycol (PEG), and carboxylated PCL (cPCL) - as synthetic substrates for culturing human iPSC-CMs. Of these, iPSC-CMs cultured on 4%PEG-96%PCL (each % indicates the corresponding molar ratio) exhibit the greatest contractility and mitochondrial function. These functional enhancements are associated with increased expression of cardiac myosin light chain-2v, cardiac troponin I and integrin alpha-7. Importantly, iPSC-CMs cultured on 4%PEG-96%PCL demonstrate troponin I (TnI) isoform switch from the fetal slow skeletal TnI (ssTnI) to the postnatal cardiac TnI (cTnI), the first report of such transition in vitro. Finally, culturing iPSC-CMs on 4%PEG-96%PCL also significantly increased expression of genes encoding intermediate filaments known to transduce integrin-mediated mechanical signals to the myofilaments. In summary, our study demonstrates that synthetic culture matrices engineered from combinatorial polymers can be utilized to promote in vitro maturation of human iPSC-CMs through the engagement of critical matrix-integrin interactions.

Current progress in nanotechnology applications for diagnosis and treatment of kidney diseases.

Significant progress has been made in nanomedicine, primarily in the form of nanoparticles, for theranostic applications to various diseases. A variety of materials, both organic and inorganic, have been used to develop nanoparticles with promise to achieve improved efficacy in medical applications as well as reduced systemic side effects compared to current standard of care medical practices. In particular, this article highlights the recent development and application of nanoparticles for diagnosing and treating nephropathologies.

Pendant allyl crosslinking as a tunable shape memory actuator for vascular applications.

Thermo-responsive shape memory polymers (SMPs) can be programmed to fit into small-bore incisions and recover their functional shape upon deployment in the body. This property is of significant interest for developing the next generation of minimally-invasive medical devices. To be used in such applications, SMPs should exhibit adequate mechanical strengths that minimize adverse compliance mismatch-induced host responses (e.g. thrombosis, hyperplasia), be biodegradable, and demonstrate switch-like shape recovery near body temperature with favorable biocompatibility. Combinatorial approaches are essential in optimizing SMP material properties for a particular application. In this study, a new class of thermo-responsive SMPs with pendant, photocrosslinkable allyl groups, x%poly(ε-caprolactone)-co-y%(α-allyl carboxylate ε-caprolactone) (x%PCL-y%ACPCL), are created in a robust, facile manner with readily tunable material properties. Thermomechanical and shape memory properties can be drastically altered through subtle changes in allyl composition. Molecular weight and gel content can also be altered in this combinatorial format to fine-tune material properties. Materials exhibit highly elastic, switch-like shape recovery near 37°C. Endothelial compatibility is comparable to tissue culture polystyrene (TCPS) and 100%PCL in vitro and vascular compatibility is demonstrated in vivo in a murine model of hindlimb ischemia, indicating promising suitability for vascular applications. STATEMENT OF SIGNIFICANCE: With the ongoing thrust to make surgeries minimally-invasive, it is prudent to develop new biomaterials that are highly compatible and effective in this workflow. Thermo-responsive shape memory polymers (SMPs) have great potential for minimally-invasive applications because SMP medical devices (e.g. stents, grafts) can fit into small-bore minimally-invasive surgical devices and recover their functional shape when deployed in the body. To realize their potential, it is imperative to devise combinatorial approaches that enable optimization of mechanical, SM, and cellular responses for a particular application. In this study, a new class of thermo-responsive SMPs is created in a robust, facile manner with readily tunable material properties. Materials exhibit excellent, switch-like shape recovery near body temperature and promising biocompatibility for minimally-invasive vascular applications.

ROS-cleavable proline oligomer crosslinking of polycaprolactone for pro-angiogenic host response.

A reactive oxygen species (ROS)-degradable scaffold is fabricated by crosslinking biocompatible, hydrolytically-degradable poly(ε-caprolactone) (PCL) with a ROS-degradable oligoproline peptide, KP7K. The ROS-mediated degradability triggers favorable host responses of the scaffold including improved cell infiltration and angiogenesis in vivo, indicating its unique advantages for tissue engineering applications.

Femtosecond laser-patterned nanopore arrays for surface-mediated peptide treatment.

The major goal of this study was to create easy-to-use, reusable substrates capable of storing any peptides or bioactive molecules for a desired period of time until cells uptake them without the need for bioactive molecule or peptide-specific techniques. Nanopore arrays of uniform size and distribution were machined into fused silica substrates using femtosecond laser ablation and loaded with peptides by simple adsorption. The nanopore substrates were validated by examining the effect of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) loaded nanopores on macrophage phagocytosis and intracellular production of reactive oxygen species (ROS) with and without the pro-inflammatory lipopolysaccharide (LPS). Our results demonstrated that nanopores were generated in a uniform array fashion. Ac-SDKP peptides were stably stored in nanopores and internalized by macrophages. Significant reductions in ROS production and phagocytosis in macrophages were observed over control substrates, even in combination with LPS stimulation, indicating that loading Ac-SDKP peptides in pores significantly improved the anti-inflammatory effects. FROM THE CLINICAL EDITOR: This team of scientists intended to create easy-to-use, reusable substrates for storing peptides or bioactive molecules for a desired period of time before cellular uptake occurs, and without the need for bioactive molecule or peptide-specific techniques. They demonstrate the successful generation of nanopores in a uniform array that stably stores Ac-SDKP peptides in the nanopores. When peptides were internalized by macrophages, significant reductions in ROS production and phagocytosis were observed, indicating improved anti-inflammatory effects.

Decoupling polymer properties to elucidate mechanisms governing cell behavior.

Determining how a biomaterial interacts with cells ("structure-function relationship") reflects its eventual clinical applicability. Therefore, a fundamental understanding of how individual material properties modulate cell-biomaterial interactions is pivotal to improving the efficacy and safety of clinically translatable biomaterial systems. However, due to the coupled nature of material properties, their individual effects on cellular responses are difficult to understand. Structure-function relationships can be more clearly understood by the effective decoupling of each individual parameter. In this article, we discuss three basic decoupling strategies: (1) surface modification, (2) cross-linking, and (3) combinatorial approaches (i.e., copolymerization and polymer blending). Relevant examples of coupled material properties are briefly reviewed in each section to highlight the need for improved decoupling methods. This follows with examples of more effective decoupling techniques, mainly from the perspective of three primary classes of synthetic materials: polyesters, polyethylene glycol, and polyacrylamide. Recent strides in decoupling methodologies, especially surface-patterning and combinatorial techniques, offer much promise in further understanding the structure-function relationships that largely govern the success of future advancements in biomaterials, tissue engineering, and drug delivery.