Flexible conducting polymer-based cellulose substrates for on-skin applications.

Flexible electroactive cellulose-based substrates were successfully fabricated via electropolymerization of either polypyrrole (PPy) or poly(3,4-ethylenedioxythiophene) (PEDOT) in the presence of sodium dodecyl sulphate (SDS) onto platinum-coated cellulose substrates. Results showed that the conductive polymers were evenly deposited onto the platinum-coated cellulose substrates, respectively without compromising the submicro roughness topography of the substrate. In fact, nanoroughness feature was formed by the deposition of conductive polymers on the individual fibres of the cellulose paper, both of which are highly important in regulating cell adhesion, proliferation and migration. The various electroactive cellulose-based papers exhibited good mechanical and structural properties as well as good cytocompatibility by supporting the attachment and proliferation of immortalized human keratinocytes (HaCaT cells). In addition, copper (Cu2+) and the zinc (Zn2+) ions were proved to be successfully doped into these PPy- and PEDOT-cellulose substrates. The PEDOT resulted in the higher doping of Cu2+ and Zn2+ ions, which was confirmed by the ions release studies. Furthermore, the PEDOT-cellulose substrates exhibited significantly higher mechanical properties, better initial cell attachment and higher electrochemical capacitance as compared to PPy-cellulose substrates. Overall, the results suggested that the PEDOT-cellulose substrates could potentially be a better choice of smart skin dressings, integration interface between skin and artificial devices or implantable electronic materials.

Hyaluronan Receptor LYVE-1-Expressing Macrophages Maintain Arterial Tone through Hyaluronan-Mediated Regulation of Smooth Muscle Cell Collagen.

The maintenance of appropriate arterial tone is critically important for normal physiological arterial function. However, the cellular and molecular mechanisms remain poorly defined. Here, we have shown that in the mouse aorta, resident macrophages prevented arterial stiffness and collagen deposition in the steady state. Using phenotyping, transcriptional profiling, and targeted deletion of Csf1r, we have demonstrated that these macrophages-which are a feature of blood vessels invested with smooth muscle cells (SMCs) in both mouse and human tissues-expressed the hyaluronan (HA) receptor LYVE-l. Furthermore, we have shown they possessed the unique ability to modulate collagen expression in SMCs by matrix metalloproteinase MMP-9-dependent proteolysis through engagement of LYVE-1 with the HA pericellular matrix of SMCs. Our study has unveiled a hitherto unknown homeostatic contribution of arterial LYVE-1+ macrophages through the control of collagen production by SMCs and has identified a function of LYVE-1 in leukocytes.

Hybrid Biomimetic Interfaces Integrating Supported Lipid Bilayers with Decellularized Extracellular Matrix Components.

This paper describes the functionalization of solid supported phospholipid bilayer with decellularized extracellular matrix (dECM) components, toward the development of biomimetic platforms that more closely mimic the cell surface environment. The dECM was obtained through a combination of chemical and enzymatic treatments of mouse adipose tissue that contains collagen, fibronectin, and glycosaminoglycans (GAGs). Using amine coupling chemistry, the dECM components were attached covalently to the surface of a supported lipid bilayer containing phospholipids with reactive carboxylic acid headgroups. The bilayer formation and the kinetics of subsequent dECM conjugation were monitored by quartz crystal microbalance with dissipation (QCM-D). Fluorescence recovery after photobleaching (FRAP) confirmed the fluidity of the membrane after functionalization with dECM. The resulting hybrid biomimetic interface supports the attachment and survival of the human hepatocyte Huh 7.5 and maintains the representative hepatocellular function. Importantly, the platform is suitable for monitoring the lateral organization and clustering of cell-binding ligands and growth factor receptors in the presence of the rich biochemical profile of tissue-derived ECM components.

Fish scale-derived collagen patch promotes growth of blood and lymphatic vessels in vivo.

In this study, Type I collagen was extracted from fish scales asa potential alternative source of collagen for tissue engineering applications. Since unmodified collagen typically has poor mechanical and degradation stability both in vitro and in vivo, additional methylation modification and 1,4-butanediol diglycidyl ether (BDE) crosslinking steps were used to improve the physicochemical properties of fish scale-derived collagen. Subsequently, in vivo studies using a murine model demonstrated the biocompatibility of the different fish scale-derived collagen patches. In general, favorable integration of the collagen patches to the surrounding tissues, with good infiltration of cells, blood vessels (BVs) and lymphatic vessels (LVs) were observed under growth factor-free conditions. Interestingly, significantly higher (p<0.05) number of LVs was found to be more abundant around collagen patches with methylation modification and BDE crosslinking. Overall, we have demonstrated the potential application of fish scale-derived collagen as a promising scaffolding material for various biomedical applications. STATEMENT OF SIGNIFICANCE: Currently the most common sources of collagen are of bovine and porcine origins, although the industrial use of collagen obtained from non-mammalian species is growing in importance, particularly since they have a lower risk of disease transmission and are not subjected to any cultural or religious constraints. However, unmodified collagen typically has poor mechanical and degradation stability both in vitro and in vivo. Hence, in this study, Type I collagen was successfully extracted from fish scales and chemically modified and crosslinked. In vitro studies showed overall improvement in the physicochemical properties of the material, whilst in vivo implantation studies showed improvements in the growth of blood and lymphatic host vessels in the vicinity of the implants.

Angiopoietin-like 4 induces a ß-catenin-mediated upregulation of ID3 in fibroblasts to reduce scar collagen expression.

In adult skin wounds, collagen expression rapidly re-establishes the skin barrier, although the resultant scar is aesthetically and functionally inferior to unwounded tissue. Although TGFß signaling and fibroblasts are known to be responsible for scar-associated collagen production, there are currently no prophylactic treatments for scar management. Fibroblasts in crosstalk with wound keratinocytes orchestrate collagen expression, although the precise paracrine pathways involved remain poorly understood. Herein, we showed that the matricellular protein, angiopoietin-like 4 (ANGPTL4), accelerated wound closure and reduced collagen expression in diabetic and ANGPTL4-knockout mice. Similar observations were made in wild-type rat wounds. Using human fibroblasts as a preclinical model for mechanistic studies, we systematically elucidated that ANGPTL4 binds to cadherin-11, releasing membrane-bound ß-catenin which translocate to the nucleus and transcriptionally upregulate the expression of Inhibitor of DNA-binding/differentiation protein 3 (ID3). ID3 interacts with scleraxis, a basic helix-loop-helix transcription factor, to inhibit scar-associated collagen types 1α2 and 3α1 production by fibroblasts. We also showed ANGPTL4 interaction with cadherin-11 in human scar tissue. Our findings highlight a central role for matricellular proteins such as ANGPTL4 in the attenuation of collagen expression and may have a broader implication for other fibrotic pathologies.

Supercritical carbon dioxide extracted extracellular matrix material from adipose tissue.

Adipose tissue is a rich source of extracellular matrix (ECM) material that can be isolated by delipidating and decellularizing the tissue. However, the current delipidation and decellularization methods either involve tedious and lengthy processes or require toxic chemicals, which may result in the elimination of vital proteins and growth factors found in the ECM. Hence, an alternative delipidation and decellularization method for adipose tissue was developed using supercritical carbon dioxide (SC-CO2) that eliminates the need of any harsh chemicals and also reduces the amount of processing time required. The resultant SC-CO2-treated ECM material showed an absence of nuclear content but the preservation of key proteins such as collagen Type I, collagen Type III, collagen Type IV, elastin, fibronectin and laminin. In addition, other biological factors such as glycosaminoglycans (GAGs) and growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) were also retained. Subsequently, the resulting SC-CO2-treated ECM material was used as a bioactive coating on tissue culture plastic (TCP). Four different cell types including adipose tissue-derived mesenchymal stem cells (ASCs), human umbilical vein endothelial cells (HUVECs), immortalized human keratinocyte (HaCaT) cells and human monocytic leukemia cells (THP-1) were used in this study to show that the SC-CO2-treated ECM coating can be potentially used for various biomedical applications. The SC-CO2-treated ECM material showed improved cell-material interactions for all cell types tested. In addition, in vitro scratch wound assay using HaCaT cells showed that the presence of SC-CO2-treated ECM material enhanced keratinocyte migration whilst the in vitro cellular studies using THP-1-derived macrophages showed that the SC-CO2-treated ECM material did not evoke pro-inflammatory responses from the THP-1-derived macrophages. Overall, this study shows the efficacy of SC-CO2 method for delipidation and decellularization of adipose tissue whilst retaining its ECM and its subsequent utilization as a bioactive surface coating material for soft tissue engineering, angiogenesis and wound healing applications.

A multi-material coating containing chemically-modified apatites for combined enhanced bioactivity and reduced infection via a drop-on-demand micro-dispensing technique.

Prevention of infection and enhanced osseointegration are closely related, and required for a successful orthopaedic implant, which necessitate implant designs to consider both criteria in tandem. A multi-material coating containing 1:1 ratio of silicon-substituted hydroxyapatite and silver-substituted hydroxyapatite as the top functional layer, and hydroxyapatite as the base layer, was produced via the drop-on-demand micro-dispensing technique, as a strategic approach in the fight against infection along with the promotion of bone tissue regeneration. The homogeneous distribution of silicon-substituted hydroxyapatite and silver-substituted hydroxyapatite micro-droplets at alternate position in silicon-substituted hydroxyapatite-silver-substituted hydroxyapatite/hydroxyapatite coating delayed the exponential growth of Staphylococcus aureus for up to 24 h, and gave rise to up-regulated expression of alkaline phosphatase activity, type I collagen and osteocalcin as compared to hydroxyapatite and silver-substituted hydroxyapatite coatings. Despite containing reduced amounts of silicon-substituted hydroxyapatite and silver-substituted hydroxyapatite micro-droplets over the coated area than silicon-substituted hydroxyapatite and silver-substituted hydroxyapatite coatings, silicon-substituted hydroxyapatite-silver-substituted hydroxyapatite/hydroxyapatite coating exhibited effective antibacterial property with enhanced bioactivity. By exhibiting good controllability of distributing silicon-substituted hydroxyapatite, silver-substituted hydroxyapatite and hydroxyapatite micro-droplets, it was demonstrated that drop-on-demand micro-dispensing technique was capable in harnessing the advantages of silver-substituted hydroxyapatite, silicon-substituted hydroxyapatite and hydroxyapatite to produce a multi-material coating along with enhanced bioactivity and reduced infection.

Comparative study of adipose-derived stem cells and bone marrow-derived stem cells in similar microenvironmental conditions.

Mesenchymal stem cells (MSCs), which were first isolated from the bone marrow, are now being extracted from various other tissues in the body, including the adipose tissue. The current study presents systematic evidence of how the adipose tissue-derived stem cells (ASCs) and bone marrow-derived mesenchymal stem cells (Bm-MSCs) behave when cultured in specific pro-adipogenic microenvironments. The cells were first characterized and identified as MSCs in terms of their morphology, phenotypic expression, self-renewal capabilities and multi-lineage potential. Subsequently, the proliferation and gene expression profiles of the cell populations cultured on two-dimensional (2D) adipose tissue extracellular matrix (ECM)-coated tissue culture plastic (TCP) and in three-dimensional (3D) AlgiMatrix® microenvironments were analyzed. Overall, it was found that adipogenesis was triggered in both cell populations due to the presence of adipose tissue ECM. However, in 3D microenvironments, ASCs and Bm-MSCs were predisposed to the adipogenic and osteogenic lineages respectively. Overall, findings from this study will contribute to ongoing efforts in adipose tissue engineering as well as provide new insights into the role of the ECM and cues provided by the immediate microenvironment for stem cell differentiation.

Comparative Study of Adipose-Derived Stem Cells From Abdomen and Breast.

BACKGROUND: Abdominal tissue enriched with adipose-derived stem cells (ASCs) is often used in cell-assisted lipotransfer procedures for breast reconstruction. However, as the tissue microenvironment and stem cell niche play important roles in defining the characteristics of the resident cells, it is hypothesized that the stem cell population present in the donor abdominal tissue has dissimilar properties as compared with the cells in the recipient breast tissue, which may ultimately affect the long-term success of the graft. METHODS: Adipose-derived stem cells were isolated from breast and abdominal fat tissues and characterized for mesenchymal-specific cell surface markers, and their population doubling, colony-forming capabilities, and proliferative properties were compared. The multilineage potential of both cell populations was also investigated. RESULTS: Adipose-derived stem cells from both tissue sites were found to possess similar marker expression and multilineage differentiation potential. However, breast fat-derived ASCs were observed to have a higher self-renewal capability and an unstable population doubling as compared with abdominal fat-derived ASCs. Gene expression studies revealed that the breast fat-derived ASCs were predisposed to the osteogenic lineage and the abdominal fat-derived ASCs to the adipogenic lineage. CONCLUSIONS: Cells derived from both fat tissues possess different characteristics in terms of their growth kinetics and predisposition to the osteolineages and adipolineages. In particular, ASCs from the abdominal tissue appear to contribute to adipose tissue turnover, whereas ASCs from breast tissue, if used for cell-assisted fat grafting, may potentially be responsible for complications in fat grafting, such as oil cysts, calcifications, fat necrosis, and tumors.

Single-step synthesis of heparin-doped polypyrrole nanoparticles for delivery of angiogenic factor.

AIM: To perform one-pot synthesis of heparin-immobilized polypyrrole (PPy) nanoparticles and evaluate the use of these nanoparticles for the delivery of VEGF. MATERIALS & METHODS: Heparin-stabilized synthesis of PPy nanoparticles was performed via oxidative polymerization. VEGF-bound PPy-heparin nanoparticles were delivered to endothelial cells and bioactivity of VEGF was assessed by Matrigel tube formation. RESULTS: Size-controllable synthesis of heparin-doped PPy nanoparticles was achieved, and heparin promoted the conjugation of VEGF. Angiogenic activity of the VEGF-conjugated PPy nanoparticles was verified. CONCLUSION: Heparin-doped PPy nanoparticles can be synthesized using one-pot reaction and provide a delivery platform by which VEGF can be conjugated onto.

Cell-secreted extracellular matrix formation and differentiation of adipose-derived stem cells in 3D alginate scaffolds with tunable properties.

Three dimensional (3D) alginate scaffolds with tunable mechanical and structural properties are explored for investigating the effect of the scaffold properties on stem cell behavior and extracellular matrix (ECM) formation. Varying concentrations of crosslinker (20 - 60%) are used to tune the stiffness, porosity, and the pore sizes of the scaffolds post-fabrication. Enhanced cell proliferation and adipogenesis occur in scaffolds with 3.52 ± 0.59 kPa stiffness, 87.54 ± 18.33% porosity and 68.33 ± 0.88 µm pore size. On the other hand, cells in scaffolds with stiffness greater than 11.61 ± 1.74 kPa, porosity less than 71.98 ± 6.25%, and pore size less than 64.15 ± 4.34 µm preferentially undergo osteogenesis. When cultured in differentiation media, adipose-derived stem cells (ASCs) undergoing terminal adipogenesis in 20% firming buffer (FB) scaffolds and osteogenesis in 40% and 60% FB scaffolds show the highest secretion of collagen as compared to other groups of scaffolds. Overall, this study demonstrates the three-way relationship between 3D scaffolds, ECM composition, and stem cell differentiation.

Surface modification of PVDF using non-mammalian sources of collagen for enhancement of endothelial cell functionality.

Although polyvinylidene fluoride (PVDF) is non-toxic and stable in vivo, its hydrophobic surface has limited its bio-applications due to poor cell-material interaction and thrombus formation when used in blood contacting devices. In this study, surface modification of PVDF using naturally derived non-mammalian collagen was accomplished via direct surface-initiated atom transfer radical polymerisation (SI-ATRP) to enhance its cytocompatibility and hemocompatibility. Results showed that Type I collagen was successfully extracted from fish scales and bullfrog skin. The covalent immobilisation of fish scale-derived collagen (FSCOL) and bullfrog skin-derived collagen (BFCOL) onto the PVDF surface improves the attachment and proliferation of human umbilical vein endothelial cells (HUVECs). Furthermore, both FSCOL and BFCOL had comparable anti-thrombogenic profiles to that of commercially available bovine collagen (BVCOL). Also, cell surface expression of the leukocyte adhesion molecule was lower on HUVECs cultured on non-mammalian collagen surfaces than on BVCOL, which is an indication of lower pro-inflammatory response. Overall, results from this study demonstrated that non-mammalian sources of collagen could be used to confer bioactivity to PVDF, with comparable cell-material interactions and hemocompatibility to BVCOL. Additionally, higher expression levels of Type IV collagen in HUVECs cultured on FSCOL and BFCOL were observed as compared to BVCOL, which is an indication that the non-mammalian sources of collagen led to a better pro-angiogenic properties, thus making them suitable for blood contacting applications.

A Periosteum-Inspired 3D Hydrogel-Bioceramic Composite for Enhanced Bone Regeneration .

A 3D injectable hydrogel-bioceramic composite consisting of gelatin-3-(4-hydroxyphenyl) propionic acid (Gtn-HPA) and carboxymethyl cellulose-tyramine (CMC-Tyr), incorporated with fish scale-derived calcium phosphate (CaP), is developed for bone applications. The hydrogel-bioceramic composite has significantly improved the elastic modulus compared to the non-filled hydrogel, of which the addition of 10 w/v% CaP showed zero order fluorescein isothiocyanate (FITC)-dextran release profile and a significantly higher proliferation rate of encapsulated cells. All the samples promote the nucleation and growth of CaP minerals when exposed to 1× SBF. Overall, the hydrogel-bioceramic composite with 10 w/v% CaP can potentially be used as a periosteum-mimicking membrane to facilitate bone regeneration.

Development of a miniaturized stimulation device for electrical stimulation of cells.

BACKGROUND: Directing cell behaviour using controllable, on-demand non-biochemical methods, such as electrical stimulation is an attractive area of research. While there exists much potential in exploring different modes of electrical stimulation and investigating a wider range of cellular phenomena that can arise from electrical stimulation, progress in this field has been slow. The reasons for this are that the stimulation techniques and customized setups utilized in past studies have not been standardized, and that current approaches to study such phenomena rely on low throughput platforms with restricted variability of waveform outputs. RESULTS: Here, we first demonstrated how a variety of cellular responses can be elicited using different modes of DC and square waveform stimulation. Intracellular calcium levels were found to be elevated in the neuroblast cell line SH-SY5Y during stimulation with 5 V square waves and, stimulation with 150 mV/mm DC fields and 1.5 mA DC current resulted in polarization of protein kinase Akt in keratinocytes and elongation of endothelial cells, respectively. Next, a miniaturized stimulation device was developed with an integrated cell chamber array to output multiple discrete stimulation channels. A frequency dividing circuit implemented on the device provides a robust system to systematically study the effects of multiple output frequencies from a single input channel. CONCLUSION: We have shown the feasibility of directing cellular responses using various stimulation waveforms, and developed a modular stimulation device that allows for the investigation of multiple stimulation parameters, which previously had to be conducted with different discrete equipment or output channels. Such a device can potentially spur the development of other high throughput platforms for thorough investigation of electrical stimulation parameters on cellular responses.

Imparting electroactivity to polycaprolactone fibers with heparin-doped polypyrrole: Modulation of hemocompatibility and inflammatory responses.

Hemocompatibility, anti-inflammation and anti-thrombogenicity of acellular synthetic vascular grafts remains a challenge in biomaterials design. Using electrospun polycaprolactone (PCL) fibers as a template, a coating of polypyrrole (PPy) was successfully polymerized onto the fiber surface. The fibers coated with heparin-doped PPy (PPy-HEP) demonstrated better electroactivity, lower surface resistivity (9-10-fold) and better anti-coagulation response (non-observable plasma recalcification after 30min vs. recalcification at 8-9min) as compared to fibers coated with pristine PPy. Red blood cell compatibility, measured by% hemolysis, was greatly improved on PPy-HEP-coated PCL in comparison to uncoated PCL (3.9±2.1% vs. 22.1±4.1%). PPy-HEP-coated PCL fibers also exhibited higher stiffness values (6.8±0.9MPa vs. 4.2±0.8MPa) as compared to PCL fibers, but similar tensile strengths. It was also observed that the application of a low alternating current led to a 4-fold reduction of platelet activation (as quantitated by CD62p expression) for the PPy-HEP-coated fibers as compared to non-stimulated conditions. In parallel, a reduction in the leukocyte adhesion to both pristine PPy-coated and PPy-HEP-coated fibers was observable with AC stimulation. Overall, a new strategy involving the use of hemocompatible conducting polymers and electrical stimulation to control thrombogenicity and inflammatory responses for synthetic vascular graft designs was demonstrated.

Polymer-Enriched 3D Graphene Foams for Biomedical Applications.

Graphene foams (GFs) are versatile nanoplatforms for biomedical applications because of their excellent physical, chemical, and mechanical properties. However, the brittleness and inflexibility of pristine GF (pGF) are some of the important factors restricting their widespread application. Here, a chemical-vapor-deposition-assisted method was used to synthesize 3D GFs, which were subsequently spin-coated with polymer to produce polymer-enriched 3D GFs with high conductivity and flexibility. Compared to pGF, both poly(vinylidene fluoride)-enriched GF (PVDF/GF) and polycaprolactone-enriched GF (PCL/GF) scaffolds showed improved flexibility and handleability. Despite the presence of the polymers, the polymer-enriched 3D GF scaffolds retained high levels of electrical conductivity because of the presence of microcracks that allowed for the flow of electrons through the material. In addition, polymer enrichment of GF led to an enhancement in the formation of calcium phosphate (Ca-P) compounds when the scaffolds were exposed to simulated body fluid. Between the two polymers tested, PCL enrichment of GF resulted in a higher in vitro mineralization nucleation rate because the oxygen-containing functional group of PCL had a higher affinity for Ca-P deposition and formation compared to the polar carbon-fluorine (C-F) bond in PVDF. Taken together, our current findings are a stepping stone toward future applications of polymer-enriched 3D GFs in the treatment of bone defects as well as other biomedical applications.

PCL microspheres tailored with carboxylated poly(glycidyl methacrylate)-REDV conjugates as conducive microcarriers for endothelial cell expansion.

Microcarrier cell culture systems provide one of the most promising techniques for cell amplification due to their high surface area-to-volume ratio. In this study, biodegradable polycaprolactone (PCL) microspheres tethered with carboxylated poly(glycidyl methacrylate)-REDV conjugates were developed by a combination of surface-initiated atom transfer radical polymerization (ATRP) and azide-alkyne click chemistry as conducive microcarriers for rapid cell expansion of human umbilical vein endothelial cells (HUVECs). Azido-terminated poly(glycidyl methacrylate) (PGMA-N3) brushes were grafted onto the PCL microspheres by surface-initiated ATRP. Subsequent carboxylation of PGMA-N3 brushes was accomplished by azide-alkyne click reaction with hexynoic acid. REDV peptides were covalently conjugated to the pendent carboxyl groups on the side chain of carboxylated PGMA-COOH brushes via carbodiimide chemistry to enhance the cytocompatibility of the three-dimension (3D) PCL scaffolding system. Success in each functionalization step was ascertained by the measurement of attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and wet laser particle size analysis. In vitro cell-loading assay of HUVECs demonstrated a significant improvement of cell adhesion and proliferation on the REDV-immobilized PCL microsphere surfaces, and a confluent layer of HUVECs was formed after 7 days of incubation. The highly biocompatible and transportable nature of functionalized PCL microcarriers offers significant potential as a cell expansion platform.

Multifunctional REDV-conjugated zwitterionic polycarboxybetaine-polycaprolactone hybrid surfaces for enhanced antibacterial activity, anti-thrombogenicity and endothelial cell proliferation.

Ideal synthetic polymeric vascular scaffolds should provide an excellent physiological environment to facilitate cell adhesion and growth, and appropriate physicochemical properties to prevent thrombogenicity and secondary infection. In the current study, a multifunctional polycaprolactone (PCL) surface for simultaneously enhancing the adhesion and proliferation of endothelial cells (ECs), as well as inhibiting pathogenic microbial adhesion and preserving hemocompatibility was demonstrated. The achievement of such a multifunctional surface was accomplished by the conjugation of Arg-Glu-Asp-Val (REDV) short peptides to zwitterionic polycarboxybetaine brush-grafted PCL films via surface-initiated atom transfer radical polymerization (ATRP). An in vitro antibacterial test demonstrated a high antibacterial efficiency against Gram-negative E. coli on the as-synthesized REDV-conjugated zwitterionic polycarboxybetaine hybrid surfaces. In addition, the platelet adhesion assay results showed that the zwitterionic polycarboxybetaine-REDV conjugates led to the amelioration of surface hemocompatibility, and this enhancement was not negated by the conjugation of REDV. Celluar studies further revealed that the EC attachment and proliferation were substantially improved by zwitterionic polycarboxybetaine-REDV conjugation as compared to other PCL surfaces. The current multifunctional PCL hybrid surface is potentially useful in tissue engineered constructs for vascular graft applications as it allows for better initial attachment and proliferation of ECs and improved hemocompatibility, whilst simultaneously reducing graft-associated infections.

Early controlled release of peroxisome proliferator-activated receptor ß/δ agonist GW501516 improves diabetic wound healing through redox modulation of wound microenvironment.

Diabetic wounds are imbued with an early excessive and protracted reactive oxygen species production. Despite the studies supporting PPARß/δ as a valuable pharmacologic wound-healing target, the therapeutic potential of PPARß/δ agonist GW501516 (GW) as a wound healing drug was never investigated. Using topical application of polymer-encapsulated GW, we revealed that different drug release profiles can significantly influence the therapeutic efficacy of GW and consequently diabetic wound closure. We showed that double-layer encapsulated GW microparticles (PLLA:PLGA:GW) provided an earlier and sustained dose of GW to the wound and reduced the oxidative wound microenvironment to accelerate healing, in contrast to single-layered PLLA:GW microparticles. The underlying mechanism involved an early GW-mediated activation of PPARß/δ that stimulated GPx1 and catalase expression in fibroblasts. GPx1 and catalase scavenged excessive H2O2 accumulation in diabetic wound beds, prevented H2O2-induced ECM modification and facilitated keratinocyte migration. The microparticles with early and sustained rate of GW release had better therapeutic wound healing activity. The present study underscores the importance of drug release kinetics on the therapeutic efficacy of the drug and warrants investigations to better appreciate the full potential of controlled drug release.