Novel Biodegradable Polymer with Redox-Triggered Backbone Cleavage Through Sequential 1,6-Elimination and 1,5-Cyclization Reactions.

In the past decade, the self-immolative biodegradable polymer arose as a novel paradigm for its efficient degradation mechanism and vast potential for advanced biomedical applications. This study reports successful synthesis of a novel biodegradable polymer capable of self-immolative backbone cleavage. The monomer is designed by covalent conjugations of both pendant redox-trigger (p-nitrobenzyl alcohol) and self-immolative linker (p-hydroxybenzyl alcohol) to the cyclization spacer (n-2-(hydroxyethyl)ethylene diamine), which serves as the structural backbone. The polymerization of the monomer with hexamethylene diisocyanate yields a linear redox-sensitive polymer that can systemically degrade via sequential 1,6-elimination and 1,5-cyclization reactions within an effective timeframe. Ultimately, the polymer's potential for biomedical application is simulated through in vitro redox-triggered release of paclitaxel from polymeric nanoparticles.

Nanodiamonds enhance therapeutic efficacy of doxorubicin in treating metastatic hormone-refractory prostate cancer.

Enhancing therapeutic efficacy is essential for successful treatment of chemoresistant cancers such as metastatic hormone-refractory prostate cancer (HRPC). To improve the efficacy of doxorubicin (DOX) for treating chemoresistant disease, the feasibility of using nanodiamond (ND) particles was investigated. Utilizing the pH responsive properties of ND, a novel protocol for complexing NDs and DOX was developed using a pH 8.5 coupling buffer. The DOX loading efficiency, loading on the NDs, and pH responsive release characteristics were determined utilizing UV-Visible spectroscopy. The effects of the ND-DOX on HRPC cell line PC3 were evaluated with MTS and live/dead cell viability assays. ND-DOX displayed exceptional loading efficiency (95.7%) and drug loading on NDs (23.9 wt%) with optimal release at pH 4 (80%). In comparison to treatment with DOX alone, cell death significantly increased when cells were treated with ND-DOX complexes demonstrating a 50% improvement in DOX efficacy. Of the tested treatments, ND-DOX with 2.4 µg mL(-1) DOX exhibited superior efficacy (60% cell death). ND-DOX with 1.2 µg mL(-1) DOX achieved 42% cell death, which was comparable to cell death in response to 2.4 µg mL(-1) of free DOX, suggesting that NDs aid in decreasing the DOX dose necessary to achieve a chemotherapeutic efficacy. Due to its enhanced efficacy, ND-DOX can be used to successfully treat HRPC and potentially decrease the clinical side effects of DOX.

Endothelium-Mimicking Nanomatrix Coating to Enhance Endothelialization after Left Atrial Appendage Closure Device Implantation.

Blood clots (90%) originate from the left atrial appendage (LAA) in non-valvular atrial fibrillation patients and are a major cause of embolic stroke. Long-term anticoagulation therapy has been used to prevent thrombus formation, but its use is limited in patients at a high risk for bleeding complications. Thus, left atrial appendage closure (LAAC) devices for LAA occlusion are well-established as an alternative to the anticoagulation therapy. However, the anticoagulation therapy is still required for at least 45 days post-implantation to bridge the time until complete LAA occlusion by neoendocardium coverage of the device. In this study, we applied an endothelium-mimicking nanomatrix to the LAAC device membrane for delivery of nitric oxide (NO) to enhance endothelialization, with the goal of possibly being able to reduce the duration of the anticoagulation therapy. The nanomatrix was uniformly coated on the LAAC device membranes and provided sustained release of NO for up to 1 month in vitro. In addition, the nanomatrix coating promoted endothelial cell proliferation and reduced platelet adhesion compared to the uncoated device membranes in vitro. The nanomatrix-coated and uncoated LAAC devices were then deployed in a canine LAA model for 22 days as a pilot study. All LAAC devices were not completely covered by neoendocardium 22 days post-implantation. However, histology image analysis showed that the nanomatrix-coated LAAC device had thicker neoendocardium coverage compared to the uncoated device. Therefore, our in vitro and in vivo results indicate that the nanomatrix coating has the potential to enhance endothelialization on the LAAC device membrane, which could improve patient outcomes by shortening the need for extended anticoagulation treatment.

Non-equilibrium organosilane plasma polymerization for modulating the surface of PTFE towards potential blood contact applications.

We report a novel and facile organosilane plasma polymerization method designed to improve the surface characteristics of poly(tetrafluoroethylene) (PTFE). We hypothesized that the polymerized silane coating would provide an adhesive surface for endothelial cell proliferation due to a large number of surface hydroxyl groups, while the large polymer networks on the surface of PTFE would hinder platelet attachment. The plasma polymerized PTFE surfaces were then systematically characterized via different analytical techniques such as FTIR, XPS, XRD, Contact angle, and SEM. The key finding of the characterization is the time-dependent deposition of an organosilane layer on the surface of PTFE. This layer was found to provide favorable surface properties to PTFE such as a very high surface oxygen content, high hydrophilicity and improved surface mechanics. Additionally, in vitro cellular studies were conducted to determine the bio-interface properties of the plasma-treated and untreated PTFE. The important results of these experiments were rapid endothelial cell growth and decreased platelet attachment on the plasma-treated PTFE compared to untreated PTFE. Thus, this new surface modification technique could potentially address the current challenges associated with PTFE for blood contact applications, specifically poor endothelial cell growth and risk of thrombosis.

Pulp-Dentin Tissue Healing Response: A Discussion of Current Biomedical Approaches.

Dental pulp tissue exposed to mechanical trauma or cariogenic process results in root canal and/or periapical infections, and conventionally treated with root canal procedures. The more recent regenerative endodontic procedure intends to achieve effective root canal disinfection and adequate pulp-dentin tissue regeneration; however, numerous limitations are reported. Because tooth is composed of vital soft pulp enclosed by the mineralized hard tissue in a highly organized structure, complete pulp-dentin tissue regeneration has been challenging to achieve. In consideration of the limitations and unique dental anatomy, it is important to understand the healing and repair processes through inflammatory-proliferative-remodeling phase transformations of pulp-dentin tissue. Upon cause by infectious and mechanical stimuli, the innate defense mechanism is initiated by resident pulp cells including immune cells through chemical signaling. After the expansion of infection and damage to resident pulp-dentin cells, consequent chemical signaling induces pluripotent mesenchymal stem cells (MSCs) to migrate to the injury site to perform the tissue regeneration process. Additionally, innovative biomaterials are necessary to facilitate the immune response and pulp-dentin tissue regeneration roles of MSCs. This review highlights current approaches of pulp-dentin tissue healing process and suggests potential biomedical perspective of the pulp-dentin tissue regeneration.

Development of a Shape-Memory Tube to Prevent Vascular Stenosis.

Inserting a graft into vessels with different diameters frequently causes severe damage to the host vessels. Poor flow patency is an unresolved issue in grafts, particularly those with diameters less than 6 mm, because of vessel occlusion caused by disturbed blood flow following fast clotting. Herein, successful patency in the deployment of an ≈2 mm diameter graft into a porcine vessel is reported. A new library of property-tunable shape-memory polymers that prevent vessel damage by expanding the graft diameter circumferentially upon implantation is presented. The polymers undergo seven consecutive cycles of strain energy-preserved shape programming. Moreover, the new graft tube, which features a diffuser shape, minimizes disturbed flow formation and prevents thrombosis because its surface is coated with nitric-oxide-releasing peptides. Improved patency in a porcine vessel for 18 d is demonstrated while occlusive vascular remodeling occurs. These insights will help advance vascular graft design.

Nitric oxide-releasing polyurethane-PEG copolymer containing the YIGSR peptide promotes endothelialization with decreased platelet adhesion.

Thrombosis and intimal hyperplasia are the principal causes of small-diameter vascular graft failure. To improve the long-term patency of polyurethane vascular grafts, we have incorporated both poly(ethylene glycol) and a diazeniumdiolate nitric oxide (NO) donor into the backbone of polyurethane to improve thromboresistance. Additionally, we have incorporated the laminin-derived cell adhesive peptide sequence YIGSR to encourage endothelial cell adhesion and migration, while NO release encourages endothelial cell proliferation. NO production by polyurethane films under physiological conditions demonstrated biphasic release, in which an initial burst of 70% of the incorporated NO was released within 2 days, followed by sustained release over 2 months. Endothelial cell proliferation in the presence of the NO-releasing material was increased as compared to control polyurethane, and platelet adhesion to polyethylene glycol-containing polyurethane was decreased significantly with the addition of the NO donor.

Effects of the nitric oxide releasing biomimetic nanomatrix gel on pulp-dentin regeneration: Pilot study.

Successful disinfection alongside complete endodontic tissue regeneration and revascularization are the most desired clinical outcomes of regenerative endodontics. Despite reported clinical successes, significant limitations to the current regenerative endodontic procedure (REP) have been elucidated. To improve the current REP, an antibiotics and nitric oxide (NO) releasing biomimetic nanomatrix gel was developed. The study evaluates antibacterial effects of an antibiotics and NO releasing biomimetic nanomatrix gel on multispecies endodontic bacteria. Antibiotics, ciprofloxacin (CF) and metronidazole (MN) were mixed and encapsulated within the NO releasing biomimetic nanomatrix gel. The gel was synthesized and self-assembled from peptide amphiphiles containing various functional groups. Antibacterial effects of the antibiotics and NO releasing biomimetic nanomatrix gel were evaluated using bacterial viability assays involving endodontic microorganisms including clinical samples. Pulp-dentin regeneration was evaluated via animal-model experiments. The antibiotics and NO releasing biomimetic nanomatrix gel demonstrated a concentration dependent antibacterial effect. In addition, NO alone demonstrated a concentration dependent antibacterial effect on endodontic microorganism. An in vivo analysis demonstrated the antibiotics and NO releasing biomimetic nanomatrix gel promoted tooth revascularization with maturation of root canals. An optimal concentration of and NO releasing nanomatrix gel is suggested for its potential as a root treatment material for REP and an appropriate protocol for human trials. Further investigation is required to obtain a larger sample size and decide upon ideal growth factor incorporation.

Biomimetic microenvironments for regenerative endodontics.

Regenerative endodontics has been proposed to replace damaged and underdeveloped tooth structures with normal pulp-dentin tissue by providing a natural extracellular matrix (ECM) mimicking environment; stem cells, signaling molecules, and scaffolds. In addition, clinical success of the regenerative endodontic treatments can be evidenced by absence of signs and symptoms; no bony pathology, a disinfected pulp, and the maturation of root dentin in length and thickness. In spite of the various approaches of regenerative endodontics, there are several major challenges that remain to be improved: a) the endodontic root canal is a strong harbor of the endodontic bacterial biofilm and the fundamental etiologic factors of recurrent endodontic diseases, (b) tooth discolorations are caused by antibiotics and filling materials, (c) cervical root fractures are caused by endodontic medicaments, (d) pulp tissue is not vascularized nor innervated, and (e) the dentin matrix is not developed with adequate root thickness and length. Generally, current clinical protocols and recent studies have shown a limited success of the pulp-dentin tissue regeneration. Throughout the various approaches, the construction of biomimetic microenvironments of pulp-dentin tissue is a key concept of the tissue engineering based regenerative endodontics. The biomimetic microenvironments are composed of a synthetic nano-scaled polymeric fiber structure that mimics native pulp ECM and functions as a scaffold of the pulp-dentin tissue complex. They will provide a framework of the pulp ECM, can deliver selective bioactive molecules, and may recruit pluripotent stem cells from the vicinity of the pulp apex. The polymeric nanofibers are produced by methods of self-assembly, electrospinning, and phase separation. In order to be applied to biomedical use, the polymeric nanofibers require biocompatibility, stability, and biodegradability. Therefore, this review focuses on the development and application of the biomimetic microenvironments of pulp-dentin tissue among the current regenerative endodontics.

Poly(ɛ-caprolactone)/gelatin composite electrospun scaffolds with porous crater-like structures for tissue engineering.

Electrospinning has been widely used to fabricate scaffolds imitating the structure of natural extracellular matrix (ECM). However, conventional electrospinning produces tightly compacted nanofiber layers with only small superficial pores and a lack of bioactivity, which limit the usefulness of electrospinning in biomedical applications. Thus, a porous poly(ε-caprolactone) (PCL)/gelatin composite electrospun scaffold with crater-like structures was developed. Porous crater-like structures were created on the scaffold by a gas foaming/salt leaching process; this unique fiber structure had more large pore areas and higher porosity than the conventional electrospun fiber network. Various ratios of PCL/gelatin (concentration ratios: 100/0, 75/25, and 50/50) composite electrospun scaffolds with and without crater-like structures were characterized by their microstructures, surface chemistry, degradation, mechanical properties, and ability to facilitate cell growth and infiltration. The combination of PCL and gelatin endowed the scaffold with both structural stability of PCL and bioactivity of gelatin. All ratios of scaffolds with crater-like structures showed fairly similar surface chemistry, degradation rates, and mechanical properties to equivalent scaffolds without crater-like structures; however, craterized scaffolds displayed higher human mesenchymal stem cell (hMSC) proliferation and infiltration throughout the scaffolds after 7-day culture. Therefore, these results demonstrated that PCL/gelatin composite electrospun scaffolds with crater-like structures can provide a structurally and biochemically improved three-dimensional ECM-mimicking microenvironment.

A bio-inspired hybrid nanosack for graft vascularization at the omentum.

UNLABELLED: For three-dimensional tissue engineering scaffolds, the major challenges of hydrogels are poor mechanical integrity and difficulty in handling during implantation. In contrast, electrospun scaffolds provide tunable mechanical properties and high porosity; but, are limited in cell encapsulation. To overcome these limitations, we developed a "hybrid nanosack" by combination of a peptide amphiphile (PA) nanomatrix gel and an electrospun poly (ε-caprolactone) (ePCL) nanofiber sheet with porous crater-like structures. This hybrid nanosack design synergistically possessed the characteristics of both approaches. In this study, the hybrid nanosack was applied to enhance local angiogenesis in the omentum, which is required of tissue engineering scaffolds for graft survival. The ePCL sheet with porous crater-like structures improved cell and blood vessel penetration through the hybrid nanosack. The hybrid nanosack also provided multi-stage fibroblast growth factor-2 (FGF-2) release kinetics for stimulating local angiogenesis. The hybrid nanosack was implanted into rat omentum for 14days and vascularization was analyzed by micro-CT and immunohistochemistry; the data clearly demonstrated that both FGF-2 delivery and porous crater-like structures work synergistically to enhance blood vessel formation within the hybrid nanosack. Therefore, the hybrid nanosack will provide a new strategy for engineering scaffolds to achieve graft survival in the omentum by stimulating local vascularization, thus overcoming the limitations of current strategies. STATEMENT OF SIGNIFICANCE: For three-dimensional tissue engineering scaffolds, the major challenges of hydrogels are poor mechanical integrity and difficulty in handling during implantation. In contrast, electrospun scaffolds provide tunable mechanical properties and high porosity; but, are limited in cell encapsulation. To overcome these limitations, we developed a "hybrid nanosack" by combination of a peptide amphiphile (PA) nanomatrix gel and an electrospun poly (ε-caprolactone) (ePCL) nanofiber sheet with porous crater-like structures. This design synergistically possessed the characteristics of both approaches. In this study, the hybrid nanosack was applied to enhance local angiogenesis in the omentum, which is required of tissue engineering scaffolds for graft survival. The hybrid nanosack was implanted into rat omentum for 14days and vascularization was analyzed by micro-CT and immunohistochemistry. We demonstrate that both FGF-2 delivery and porous crater-like structures work synergistically to enhance blood vessel formation within the hybrid nanosack. Therefore, the hybrid nanosack will provide a new strategy for engineering scaffolds to achieve graft survival in the omentum by stimulating local vascularization, thus overcoming the limitations of current strategies.

Endothelialization of microporous YIGSR/PEG-modified polyurethaneurea.

Bioactive polyurethaneurea modified with polyethylene glycol (PEG) and the endothelial cell-adhesive peptide YIGSR was synthesized and fabricated into microporous scaffolds. This material has shown appropriate mechanical properties for vascular graft applications, resists platelet adhesion, and promotes endothelialization. In the current study, microporous scaffolds were formed by a gasfoaming and salt-leaching method. The scaffolds showed highly interconnected open pores throughout the matrices, with porosity of approximately 78% and pore sizes of 20-200 microm. The peptide modified scaffolds showed superior mechanical properties over peptide-free scaffolds (tensile strength, 1.4 +/- 0.03 versus 0.19 +/- 0.01 MPa; p < 0.01). Bovine aortic endothelial cells were seeded on the scaffolds, and cell attachment, proliferation, extracellular matrix production, and migration were investigated. Histological and scanning electron microscopy analysis showed that few cells adhered on peptide-free scaffolds, whereas confluent endothelial cell monolayers formed along the pores in peptide-modified scaffolds. DNA content, hydroxyproline production, and cell migration were also significantly greater in peptide-modified scaffolds.

Modification of polyurethaneurea with PEG and YIGSR peptide to enhance endothelialization without platelet adhesion.

Improved endothelialization without platelet adhesion is essential to enhance the long-term patency of synthetic vascular grafts and other blood-contacting devices. We have developed a dually modified polyurethaneurea by incorporating endothelial cell adhesive YIGSR peptide sequences as chain extenders and nonthrombogenic PEG as a soft segment (PUUYIGSR-PEG) in the polymer backbone. PUUYIGSR-PEG was successfully synthesized and characterized by proton NMR, FTIR, GPC, DSC, ESCA, and contact angle measurement. Despite having similar molecular weight, the peptide/PEG-modified polyurethaneurea (PUUYIGSR-PEG) showed superior mechanical properties compared to the control PEG-modified polyurethaneurea (PUUPPD-PEG). Virtually no platelet adhesion was observed on PUUYIGSR-PEG, while endothelial cell adhesion, spreading, and migration were significantly greater on PUUYIGSR-PEG compared to PUUPPD-PEG. Thus, this bioactive polymer may be an appropriate biomaterial for small diameter vascular grafts.

A Nitric Oxide-Releasing Self-Assembled Peptide Amphiphile Nanomatrix for Improving the Biocompatibility of Microporous Hollow Fibers.

Oxygenators are critical components of extracorporeal circuits used frequently in cardiopulmonary bypass and intensive care, but platelet activation and induction of a complex inflammatory response are usually observed with their use. To improve the biocompatibility of oxygenators, we developed a nitric oxide (NO)-releasing, self-assembled peptide amphiphile nanomatrix. The nanomatrix formed a homogenous coating over the microporous hollow fibers as demonstrated by scanning electron microscopy. We quantitated platelet adhesion to the artificial fibers by measuring absorbance/area of platelets (Abs/A; nm/m2) using acid phosphatase assay. There was a 17-fold decrease in platelet adhesion to the nanomatrix (Abs/A = 0.125) compared with collagen controls (Abs/A = 2.07; p < 0.05) and a 22-fold decrease compared with uncoated fibers (Abs/A = 2.75; p < 0.05). Importantly, the nanomatrix coating did not impede oxygen transfer in water through coated fiber modules (p > 0.05) in a benchtop test circuit at different flow rates as estimated by change in partial pressure of oxygen in relation to water velocity through fibers. These findings demonstrate the feasibility of coating microporous hollow fibers with a NO-releasing self-assembled amphiphile nanomatrix that may improve the biocompatibility of the hollow fibers without affecting their gas exchange capacity.

Evaluation of ciprofloxacin and metronidazole encapsulated biomimetic nanomatrix gel on Enterococcus faecalis and Treponema denticola.

BACKGROUND: A triple antibiotic mixture (ciprofloxacin; CF, metronidazole; MN, and minocycline; MC) has been used for dental root canal medicaments in pulp regeneration therapy. However, tooth discolorations, cervical root fractures, and inadequate pulp-dentin formation have been reported due to the triple antibiotic regimen. Therefore, an antibiotic encapsulated biomimetic nanomatrix gel was developed to minimize the clinical limitations and maximize a natural healing process in root canal infections. In this study, minimal bacterial concentrations (MBC) of the selected antibiotics (CF and MN) were tested in 14 representative endodontic bacterial species. Then MBC of each CF and MN were separately encapsulated within the injectable self-assembled biomimetic nanomatrix gel to evaluate antibacterial level on Enterococcus faecalis and Treponema denticola. RESULTS: Antibiotic concentrations lower than 0.2 µg/mL of CF and MN demonstrated antibacterial activity on the 14 endodontic species. Furthermore, 6 different concentrations of CF and MN separately encapsulated with the injectable self-assembled biomimetic nanomatrix gel demonstrated antibacterial activity on Enterococcus faecalis and Treponema denticola at the lowest tested concentration of 0.0625 µg/mL. CONCLUSIONS: These results suggest that each CF and MN encapsulated within the injectable self-assembled biomimetic nanomatrix gel demonstrated antibacterial effects, which could be effective for the root canal disinfection while eliminating MC. In the long term, the antibiotic encapsulated injectable self-assembled biomimetic nanomatrix gel can provide a multifunctional antibiotic delivery method with potential root regeneration. Further studies are currently underway to evaluate the effects of combined CF and MN encapsulated within the injectable self-assembled biomimetic nanomatrix gel on clinical samples.

Adult stem cells and tissue engineering strategies for salivary gland regeneration: a review.

Saliva is an important compound produced by the salivary glands and performs numerous functions. Hyposalivation (dry mouth syndrome) is a deleterious condition often resulting from radiotherapy for patients with head and neck cancer, Sjogren's Syndrome, or as a side effect of certain medications. Hyposalivation negatively affects speaking, mastication, and swallowing in afflicted patients, greatly reducing their quality of life. Current treatments for this pathology include modifying lifestyle, synthetic saliva supplementation, and the utilization of salivary gland stimulants and sialagogues. However, many of these treatments do not address the underlying issues and others are pervaded by numerous side effects. In order to address the shortcomings related to current treatment modalities, many groups have diverted their attention to utilizing tissue engineering and regenerative medicine approaches. Tissue engineering is defined as the application of life sciences and materials engineering toward the development of tissue substitutes that are capable of mimicking the structure and function of their natural analogues within the body. The general underlying strategy behind the development of tissue engineered organ substitutes is the utilization of a combination of cells, biomaterials, and biochemical cues intended to recreate the natural organ environment. The purpose of this review is to highlight current bioengineering approaches for salivary gland tissue engineering and the adult stem cell sources used for this purpose. Additionally, future considerations in regard to salivary gland tissue engineering strategies are discussed.

Evaluation of the effect of expansion and shear stress on a self-assembled endothelium mimicking nanomatrix coating for drug eluting stents in vitro and in vivo.

Coating stability is increasingly recognized as a concern impacting the long-term effectiveness of drug eluting stents (DES). In particular, unstable coatings have been brought into focus by a recently published report (Denardo et al 2012 J. Am. Med. Assoc. 307 2148-50). Towards the goal of overcoming current challenges of DES performance, we have developed an endothelium mimicking nanomatrix coating composed of peptide amphiphiles that promote endothelialization, but limit smooth muscle cell proliferation and platelet adhesion. Here, we report a novel water evaporation based method to uniformly coat the endothelium mimicking nanomatrix onto stents using a rotational coating technique, thereby eliminating residual chemicals and organic solvents, and allowing easy application to even bioabsorbable stents. Furthermore, the stability of the endothelium mimicking nanomatrix was analyzed after force experienced during expansion and shear stress under simulated physiological conditions. Results demonstrate uniformity and structural integrity of the nanomatrix coating. Preliminary animal studies in a rabbit model showed no flaking or peeling, and limited neointimal formation or restenosis. Therefore, it has the potential to improve the clinical performance of DES by providing multifunctional endothelium mimicking characteristics with structural integrity on stent surfaces.

Enhanced human endothelial progenitor cell adhesion and differentiation by a bioinspired multifunctional nanomatrix.

Endothelial progenitor cell (EPC)-capturing techniques have led to revolutionary strategies that can improve the performance of cardiovascular implant devices and engineered tissues by enhancing re-endothelialization and angiogenesis. However, these strategies are limited by controversies regarding the phenotypic identities of EPCs as well as their inability to target and prevent the other afflictions associated with current therapies, namely, thrombosis and neointimal hyperplasia. Therefore, the goal of this study was to study the efficacy of a bioinspired multifunctional nanomatrix in recruiting and promoting the differentiation of EPCs toward an endothelial lineage. The bioinspired nanomatrix combines multiple components, including self-assembled peptide amphiphiles (PAs) that include cell adhesive ligands, nitric oxide (NO)-producing donors, and enzyme-mediated degradable sequences to achieve an endothelium-mimicking character. In this study, human peripheral blood mononuclear cells (PBMNCs) were isolated and cultured on the bioinspired multifunctional nanomatrix. Initial cell adhesion, lectin staining, acetylated low-density lipoprotein uptake, and expression of endothelial markers, including CD31, CD34, von Willebrand Factor, and VEGFR2, were analyzed. The results from this study indicate that the NO releasing bioinspired multifunctional nanomatrix promotes initial adhesion of EPCs when compared to control surfaces. The expression of endothelial markers is also increased on the bioinspired multifunctional nanomatrix, suggesting that it directs the differentiation of EPCs toward an endothelial phenotype. The bioinspired nanomatrix therefore provides a novel biomaterial-based platform for capturing as well as directing EPC behavior. Therefore, this study has the potential to positively impact the patency of cardiovascular devices such as stents and vascular grafts as well as enhanced angiogenesis for ischemic or engineered tissues.

Redox-sensitive polymeric nanoparticles for drug delivery.

Bioresponsive polymeric nanoparticles have been extensively pursued for the development of tumor-targeted drug delivery. A novel redox-sensitive biodegradable polymer with "trimethyl-locked" benzoquinone was synthesized for the preparation of paclitaxel-incorporated nanoparticles. The synthesized redox-sensitive nanoparticles released paclitaxel in response to chemically triggered reduction.

Biphasic peptide amphiphile nanomatrix embedded with hydroxyapatite nanoparticles for stimulated osteoinductive response.

Formation of the native bone extracellular matrix (ECM) provides an attractive template for bone tissue engineering. The structural support and biological complexity of bone ECM are provided within a composite microenvironment that consists of an organic fibrous network reinforced by inorganic hydroxyapatite (HA) nanoparticles. Recreating this biphasic assembly, a bone ECM analogous scaffold comprising self-assembling peptide amphiphile (PA) nanofibers and interspersed HA nanoparticles was investigated. PAs were endowed with biomolecular ligand signaling using a synthetically inscribed peptide sequence (i.e., RGDS) and integrated with HA nanoparticles to form a biphasic nanomatrix hydrogel. It was hypothesized the biphasic hydrogel would induce osteogenic differentiation of human mesenchymal stem cells (hMSCs) and improve bone healing as mediated by RGDS ligand signaling within PA nanofibers and embedded HA mineralization source. Viscoelastic stability of the biphasic PA hydrogels was evaluated with different weight concentrations of HA for improved gelation. After demonstrating initial viability, long-term cellularity and osteoinduction of encapsulated hMSCs in different PA hydrogels were studied in vitro. Temporal progression of osteogenic maturation was assessed by gene expression of key markers. A preliminary animal study demonstrated bone healing capacity of the biphasic PA nanomatrix under physiological conditions using a critical size femoral defect rat model. The combination of RGDS ligand signaling and HA nanoparticles within the biphasic PA nanomatrix hydrogel demonstrated the most effective osteoinduction and comparative bone healing response. Therefore, the biphasic PA nanomatrix establishes a well-organized scaffold with increased similarity to natural bone ECM with the prospect for improved bone tissue regeneration.