Wireless electrostimulation for cancer treatment: An integrated nanoparticle/coaxial fiber mesh platform.

Cancer, namely breast and prostate cancers, is the leading cause of death in many developed countries. Controlled drug delivery systems are key for the development of new cancer treatment strategies, to improve the effectiveness of chemotherapy and tackle off-target effects. In here, we developed a biomaterials-based wireless electrostimulation system with the potential for controlled and on-demand release of anti-cancer drugs. The system is composed of curcumin-loaded poly(3,4-ethylenedioxythiophene) nanoparticles (CUR/PEDOT NPs), encapsulated inside coaxial poly(glycerol sebacate)/poly(caprolactone) (PGS/PCL) electrospun fibers. First, we show that the PGS/PCL nanofibers are biodegradable, which allows the delivery of NPs closer to the tumoral region, and have good mechanical properties, allowing the prolonged storage of the PEDOT NPs before their gradual release. Next, we demonstrate PEDOT/CUR nanoparticles can release CUR on-demand (65 % of release after applying a potential of -1.5 V for 180 s). Finally, a wireless electrostimulation platform using this NP/fiber system was set up to promote in vitro human prostate cancer cell death. We found a decrease of 67 % decrease in cancer cell viability. Overall, our results show the developed NP/fiber system has the potential to effectively deliver CUR in a highly controlled way to breast and prostate cancer in vitro models. We also show the potential of using wireless electrostimulation of drug-loaded NPs for cancer treatment, while using safe voltages for the human body. We believe our work is a stepping stone for the design and development of biomaterial-based future smarter and more effective delivery systems for anti-cancer therapy.

Preparation and properties investigation of biodegradable poly (glycerol sebacate-co-gelatin) containing nanoclay and graphene oxide for soft tissue engineering applications.

This study has attempted to systematically investigate the influence of nanoclay and graphene oxide (GO) on thermal, mechanical, hydrophobic, and, most importantly, biological properties of poly(glycerol sebacate)/gelatin (PGS/gel) nanocomposites. The PGS/gel copolymer nanocomposites were successfully synthesized via in situ polymerization, approved by rudimentary characterization methods. The nanofillers were appropriately dispersed within the elastomeric matrix according to morphological studies. Also, the fillers posed as a hydrophobic entity that slightly decreased the hydrophilic properties of PGS/gel. This could be sensed clearly in hybrid composite due to the robust network of GO and clay. Water contact angle values for gelatin-contained nanocomposites were reported in the range of 38.42° to 66.7°, indicating the hydrophilic nature of the prepared samples. Thermal and mechanical studies of nanocomposites displayed rather contradicting results as the former improved while a slight decrease in the latter was noticed compared to the pristine specimens. In dry conditions, their storage modulus was in the range of 0.94-6.4 MPa, making them suitable for mimicking some soft tissues. The swelling ratio for nanocomposites containing nanoparticles was associated with an ascending trend so that GO improved the swelling rate by up to 45%. Biological analyses, such as Ames and in vitro cell viability tests, exhibited promising outcomes. As for the mutagenesis effect, the PGS and hybrid samples showed negative results. The presence of functional groups on the nanofillers' surface positively influenced the cells' metabolic activity as well as its attachment to the matrix. After 7 days, the cell proliferation rate resulted in an 82% improvement for the GO-containing nanocomposite, significantly higher than its neat counterpart (65%). This study has shown the feasibility of the prepared bio-elastomer nanocomposites for diverse tissue engineering applications.

Surface channel patterned and endothelialized poly(glycerol sebacate) based elastomers.

Prevascularization of tissue equivalents is critical for fulfilling the need for sufficient vascular organization for nutrient and gas transport. Hence, endothelial cell culture on biomaterials is of great importance for researchers. Numerous alternate strategies have been suggested in this sense, with cell-based methods being the most commonly employed. In this study, poly (glycerol sebacate) (PGS) elastomers with varying crosslinking ratios were synthesized and their surfaces were patterned with channels by using laser ablation technique. In order to determine an ideal material for cell culture studies, the elastomers were subsequently mechanically, chemically, and biologically characterized. Following that, human umbilical vein endothelial cells (HUVECs) were seeded into the channels established on the PGS membranes and cultured under various culture conditions to establish the optimal culture parameters. Lastly, the endothelial cell responses to the synthesized PGS elastomers were evaluated. Remarkable cell proliferation and impressive cellular organizations were noticed on the constructs created as part of the investigation. On the concrete output of this research, arrangements in various geometries can be created by laser ablation method and the effects of various molecules, drugs or agents on endothelial cells can be evaluated. The platforms produced can be employed as an intermediate biomaterial layer containing endothelial cells for vascularization of tissue-engineered structures, particularly in layer-by-layer tissue engineering approaches.

Micropatterned conductive elastomer patch based on poly (glycerol sebacate)-graphene for cardiac tissue repair.

Preparing a micropatterned elastomer film with characteristics that can simulate the mechanical properties, anisotropy, and electroactivity of natural myocardial tissues is crucial in cardiac tissue engineering after myocardial infarction (MI). Therefore, in this study, we developed several elastomeric films with a surface micropattern based on poly (glycerol sebacate) (PGS) and graphene (Gr). These films have sufficient mechanical strength (0.6 ± 0.1-3.2 ± 0.08 MPa) to withstand heartbeats, and the micropatterned structure also satisfies the natural myocardium anisotropy in the transverse and vertical. Moreover, Gr makes these films conductive (up to 5.80 × 10-7S m-1), which is necessary for the conduction of electrical signals between cardiomyocytes and the cardiac tissue. Furthermore, they have good cytocompatibility and can promote cell proliferation in H9c2 rat cardiomyocyte cell lines.In vivotest results indicate that these films have good biocompatibility. Notably, a film with 1 wt% Gr content (PGS-Gr1) significantly affects the recovery of myocardial function in rats after MI. This film effectively decreased the infarct size and degree of myocardial fibrosis and reduced collagen deposition. Echocardiographic evaluation showed that after treatment with this film, the left ventricular internal dimension (LVID) in systole and LVID in diastole of rats exhibited a significant downward trend, whereas the fractional shortening and ejection fraction were significantly increased compared with the control group. These data indicate that this electroactive micropatterned anisotropic elastomer film can be applied in cardiac tissue engineering.

Introducing a flexible drug delivery system based on poly(glycerol sebacate)-urethane and its nanocomposite: potential application in the prevention and treatment of oral diseases.

In this study, a novel biopolymer based on poly(glycerol sebacic)-urethane (PGS-U) and its nanocomposites containing Cloisite@30B were synthesized by facile approach in which the crosslinking was created by aliphatic hexamethylene diisocyanate (HDI) at room temperature and 80 °C. Moreover, metronidazole and tetracycline drugs were selected as target drugs and loaded into PGSU based nanocomposites. A uniform and continuous microstructure with smooth surface is observed in the case of pristine PGS-U sample. The continuity of microstructure is observed in the case of all bionanocomposites. XRD result confirmed an intercalated morphology for PGSU containing 5 wt% of clay nanoparticles with a d-spacing 3.4 nm. The increment of nanoclay content up to 5%, the ultimate tensile stress and elastic modulus were obtained nearly 0.32 and 0.83 MPa, which the latter was more than eight-fold than that of pristine PGS-U. A sustained release for both dugs was observed by 200 h. The slowest and controlled drug release rate was determined in the case of PGSU containing 5 wt% clay and cured at 80 °C. A non-Fickian diffusion can be concluded in the case of tetracycline release via PGS-U/nanoclay bionanocomposites, while a Fickian process was detected in the case of metronidazole release by PGS-U/nanoclay bionanocomposites. As a result, the designed scaffold showed high flexibility, which makes it an appropriate option for utilization in the treatment of periodontal disease.

Lipase-Catalyzed Synthesis and Characterization of Poly(glycerol sebacate).

This study demonstrated that immobilized Candida antarctica lipase B (N435) catalysis in bulk leads to higher molecular weight poly(glycerol sebacate), PGS, than self-catalyzed condensation polymerization. Since the glass-transition temperature, fragility, modulus, and strength for rubbery networks are inversely dependent on the concentration of chain ends, higher molecular weight PGS prepolymers will enable the preparation of cross-linked PGS matrices with unique mechanical properties. The evolution of molecular species during the prepolymerization step conducted at 120 °C for 24 h, prior to enzyme addition, revealed regular decreases in sebacic acid and glycerol-sebacate dimer with corresponding increases in oligomers with chain lengths from 3 to 7 units such that a homogeneous liquid substrate has resulted. At 67 h, for N435-catalyzed PGS synthesis, the carboxylic acid conversion reached 82% without formation of a gel fraction, and number-average molecular weight (Mn) and weight-average molecular weight (Mw) values reached 6000 and 59 400 g/mol, respectively. In contrast, self-catalyzed PGS condensation polymerizations required termination at 55 h to avoid gelation, reached 72% conversion, and Mn and Mw values of 2600 and 13 800 g/mol, respectively. We also report the extent that solvent fractionation can enrich PGS in higher molecular weight chains. The use of methanol as a nonsolvent increased Mn and Mw by 131.7 and 18.3%, respectively, and narrower dispersity (D) decreased by 47.7% relative to the nonfractionated product.

Influence of cross-linking time on physico-chemical and mechanical properties of bulk poly(glycerol sebacate).

In the presented study, a PGS prepolymer (pPGS) was synthesized utilizing polycondensation technique (equimolar sebacic acid:glycerol ratio, 130 °C, 24 h). Subsequently, the pPGS was thermally cross-linked in vacuum oven in 130 °C for 84 and 168 h. The cylindrical and dumbbell-shaped samples were subjected for physico-chemical and thorough mechanical analysis including tensile and compressive strength evaluation as well as dynamic mechanical thermal analysis (DMTA). The study allowed for the investigation of alteration of PGS properties during cross-linking and decay of elastomeric properties over prolonged cross-linking time. Moreover, a deconvolution in FTIR analysis allowed to glimpse into the hydrogen bonding structure of the materials which weakens during the cross-linking. The obtained results can be utilized during designing PGS-based bulk materials for biomedical application where bearing mechanical loads and tuned chemical character is of vital importance.

Fabrication and characterization of carbon aerogel/poly(glycerol-sebacate) patches for cardiac tissue engineering.

Cardiovascular diseases (CVDs) are responsible for the major number of deaths around the world. Among these is heart failure after myocardial infarction whose latest therapeutic methods are limited to slowing the end-state progression. Numerous strategies have been developed to meet the increased demand for therapies regarding CVDs. This study aimed to establish a novel electrically conductive elastomer-based composite and assess its potential as a cardiac patch for myocardial tissue engineering. The electrically conductive carbon aerogels (CAs) used in this study were derived from waste paper as a cost-effective carbon source and they were combined with the biodegradable poly(glycerol-sebacate) (PGS) elastomer to obtain an electrically conductive cardiac patch material. To the best of our knowledge, this is the first report about the conductive composites obtained by the incorporation of CAs into PGS (CA-PGS). In this context, the incorporation of the CAs into the polymeric matrix significantly improved the elastic modulus (from 0.912 MPa for the pure PGS elastomer to 0.366 MPa for the CA-PGS) and the deformability (from 0.792 MPa for the pure PGS to 0.566 MPa for CA-PGS). Overall, the mechanical properties of the obtained structures were observed similar to the native myocardium. Furthermore, the addition of CAs made the obtained structures electrically conductive with a conductivity value of 65 × 10-3S m-1which falls within the range previously recorded for human myocardium. Thein vitrocytotoxicity assay with L929 murine fibroblast cells revealed that the CA-PGS composite did not have cytotoxic characteristics. On the other hand, the studies conducted with H9C2 rat cardiac myoblasts revealed that final structures were suitable for MTE applications according to the successes in cell adhesion, cell proliferation, and cell behavior.

Poly(glycerol sebacate)-co-poly(ethylene glycol)/Gelatin Hybrid Hydrogels as Biocompatible Biomaterials for Cell Proliferation and Spreading.

Synthetic polymers have been widely employed to prepare hydrogels for biomedical applications, such as cell culture, drug delivery, and tissue engineering. However, the activity of cells cultured in the synthetic polymer-based hydrogels faces the challenges of limited cell proliferation and spreading compared to cells cultured in natural polymer-based hydrogels. To address this concern, a hybrid hydrogel strategy is demonstrated by incorporating thiolated gelatin (GS) into the norbornene-functionalized poly (glycerol sebacate)-co-polyethylene glycol (Nor_PGS-co-PEG, NPP) network to prepare highly biocompatible NPP/GS_UV hydrogels after the thiol-ene photo-crosslinking reaction. The GS introduces several desirable features (i.e., enhanced water content, enlarged pore size, increased mechanical property, and more cell adhesion sites) to the NPP/GS_UV hydrogels, facilitating the cell proliferation and spreading inside the network. Thus, the highly biocompatible NPP/GS_UV hydrogels are promising materials for cell encapsulation and tissue engineering applications. Taken together, the hybrid hydrogel strategy is demonstrated as a powerful approach to fabricate hydrogels with a highly friendly environment for cell culture, expanding the biomedical applications of hydrogels.

PGS/HAp Microporous Composite Scaffold Obtained in the TIPS-TCL-SL Method: An Innovation for Bone Tissue Engineering.

In this research, we synthesize and characterize poly(glycerol sebacate) pre-polymer (pPGS) (1H NMR, FTiR, GPC, and TGA). Nano-hydroxyapatite (HAp) is synthesized using the wet precipitation method. Next, the materials are used to prepare a PGS-based composite with a 25 wt.% addition of HAp. Microporous composites are formed by means of thermally induced phase separation (TIPS) followed by thermal cross-linking (TCL) and salt leaching (SL). The manufactured microporous materials (PGS and PGS/HAp) are then subjected to imaging by means of SEM and µCT for the porous structure characterization. DSC, TGA, and water contact angle measurements are used for further evaluation of the materials. To assess the cytocompatibility and biological potential of PGS-based composites, preosteoblasts and differentiated hFOB 1.19 osteoblasts are employed as in vitro models. Apart from the cytocompatibility, the scaffolds supported cell adhesion and were readily populated by the hFOB1.19 preosteoblasts. HAp-facilitated scaffolds displayed osteoconductive properties, supporting the terminal differentiation of osteoblasts as indicated by the production of alkaline phosphatase, osteocalcin and osteopontin. Notably, the PGS/HAp scaffolds induced the production of significant amounts of osteoclastogenic cytokines: IL-1ß, IL-6 and TNF-α, which induced scaffold remodeling and promoted the reconstruction of bone tissue. Initial biocompatibility tests showed no signs of adverse effects of PGS-based scaffolds toward adult BALB/c mice.

Blood compatibility and cell response improvement of poly glycerol sebacate/poly lactic acid scaffold for vascular graft applications.

Plasma surface modification is one of the new methods for improving the surface properties of the scaffold and accelerating tissue regeneration. The aim of this study was to create poly glycerol sebacate/poly lactic acid (PGS/PLA) composite scaffold by electrospun method and modified the scaffold by oxygen plasma for use as a vascular graft. Plasma surface modified PGS/PLA scaffold morphology study showed relatively uniform fibers with an average diameter of 637 ± 149.4 nm and porosity of 82%. The mechanical evaluation of the PGS/PLA scaffold showed properties close to the natural vessels. Atomic force microscopy images exhibited an increase in the roughness of the scaffold after plasma surface modification; however, hemocompatibility studies revealed that it had no adverse effect on blood compatibility. Wettability studies revealed the superhydrophilic property of the modified scaffold (contact angle near to zero). Besides, the human umbilical vein endothelial cells proliferation and adhesion were improved significantly. Obtaining mechanical properties near to the natural vessels due to the suitable composition and significant improvement in blood compatibility and cell growth make the modified PGS/PLA composite a suitable candidate for vascular tissue regeneration.

A randomized controlled preclinical trial on 3 interposal temporomandibular joint disc implants: TEMPOJIMS-Phase 2.

The effort to develop an effective and safe temporomandibular joint (TMJ) disc substitute has been one of the mainstreams of tissue engineering. Biodegradable customized scaffolds could approach safety and effectiveness to regenerate a new autologous disc, rather than using non-biodegradable materials. However, it is still technically challenging to mimic the biomechanical properties of the native disc with biodegradable polymers. In this study, new 3D tailored TMJ disc implants were developed: (1) Poly(glycerol sebacate) (PGS) scaffold reinforced with electrospun Poly(εcaprolactone) (PCL) fibers on the outer surface (PGS+PCL); (2) PCL and polyethylene glycol diacrylate (PEGDA) (PCL+PEGDA); and (3) PCL. The TMJ implants were tested in a randomized preclinical trial, conducted in 24 black Merino sheep TMJ, perfoming bilateral interventions. Histologic, imaging, and kinematics analysis was performed. No statistical changes were observed between the PGS+PCL disc and the control group. The PCL+PEGDA and PCL groups were associated with statistical changes in histology (p = 0.004 for articular cartilage mid-layer; p = 0.019 for structure changes and p = 0.017 for cell shape changes), imaging (p = 0.027 for global appreciation) and dangerous material fragmentation was observed. No biomaterial particles were observed in the multi-organ analysis in the different groups. The sheep confirmed to be a relevant animal model for TMJ disc surgery and regenerative approaches. The PCL and PCL+PEGDA discs presented a higher risk to increase degenerative changes, due to material fragmentation. None of the tested discs regenerate a new autologous disc, however, PGS+PCL was safe, demonstrated rapid resorption, and was capable to prevent condyle degenerative changes.

Citrate Crosslinked Poly(Glycerol Sebacate) with Tunable Elastomeric Properties.

Poly(glycerol-sebacate) (PGS) is a biodegradable elastomer known for its mechanical properties and biocompatibility for soft tissue engineering. However, harsh thermal crosslinking conditions are needed to make PGS devices. To facilitate the thermal crosslinking, citric acid is explored as a crosslinker to form poly(glycerol sebacate citrate) (PGSC) elastomers. The effects of varying citrate contents and curing times are investigated on the mechanical properties, elasticity, degradation, and hydrophilicity. To examine the potential presence of unreacted citric acid, material acidity is monitored in relation to the citrate content and curing times. It is discovered that a low citrate content and a short curing time produce PGSC with tunable mechanical characteristics similar to PGS with enhanced elasticity. The materials demonstrate good cytocompatibility with human umbilical vein endothelial cells similar to the PGS control. The research study suggests that PGSC is a potential candidate for large-scale biomedical applications because of the quick thermal crosslink and tunable elastomeric properties.

Low-Hysteresis and Ultrasensitive Microcellular Structures for Wearable Electronic Applications.

Wearable technologies offer the opportunity to record human physiological signals in real time, in a noninvasive way, and the data can be used to aid in the early detection of abnormal health conditions. Here, we demonstrate how the interconnected porosity can be used to increase the sensitivity and linearity of capacitive pressure sensors. The finite element analysis supports the experimental observation that the movement of air during the dynamic mechanical loading is responsible for the high sensitivity observed (0.18 ± 0.01 kPa-1) when compared with the solid poly(glycerol sebacate) sensor (0.0042 ± 0.0002 kPa-1). The porous sensors present strain insensitivity and remarkable linearity over the entire range of applied mechanical pressure (0-6 kPa), capable of detecting both static and dynamic mechanical stimuli (17 nm/s), and a response time of 50 ms, without evidence of fatigue or electrical hysteresis over 10,000 mechanical cycles. The outstanding features of the porous sensors can find a broad range of applications in real-time health monitoring, from demanding movements like walking/running, to small deformations resulting from breathing or heart beating. The ultrasensitive microcellular structures synthesized in this study can be applied to other types of sensing transductions to obtain tunable and function-specific sensors with high sensitivity.

Effect of different exposure times on physicochemical, mechanical and biological properties of PGS scaffolds treated with plasma of iodine-doped polypyrrole.

Polyglycerol sebacate (PGS) scaffolds obtained using a leaching technique were modified with iodine-doped polypyrrole (PPy-I) in a plasma reactor in order to study the effect of exposure time on the cell viability of hDPSCs. SEM analysis showed the formation and growth of PPy-I particles as the exposure time was increased, while FTIR and XPS analysis revealed the presence of -NH- and N+ groups in the chemical composition of the surfaces, relating to the increase in the amount of PPY-I particles. The water contact angle measurements showed an increase in the scaffold's hydrophilicity with greater exposure times which was also attributed to the rising of PPy-I particles. It was also observed that PPy-I promotes the rigidity of the treated PGS scaffolds. when in direct contact with treated PGS scaffolds, cell viability improved with respect to non-treated scaffolds, however only at shorter time exposures. Extracts of plasma-treated PGS scaffolds showed high cytotoxicity as the time exposure to plasma treatment was increased.

The Effectively Simultaneous Production of Cello-oligosaccharide and Glucose Mono-decanoate from Lignocellulose by Enzymatic Esterification.

Cello-oligosaccharide has drawn an increasing attention as the nutritional ingredients of dietary supplements, whose quality is affected by the concentration of monosaccharide. In the present study, an effective process was developed for the simultaneous production of cello-oligosaccharide and glucose mono-decanoate from lignocellulose by enzymatic esterification. During the process, the excessive glucose in cello-oligosaccharide was converted into glucose mono-decanoate, which is a well-known biodegradable nonionic surfactant. The filter paper was initially used as the model to investigate the feasibility of the process, in which the purity of resultant cello-oligosaccharide was increased from 33.3% to 74.3%, simultaneously producing glucose mono-decanoate with a purity of 92.3%. Further verification of 3 kinds of lignocelluloses (switchgrass, cornstalk, and reed) also indicated a good performance of the process. The present process provided an effective strategy to increase the purity of resultant cello-oligosaccharide with the simultaneous production of high value-added products of sugar monoester. Graphical Abstract Simultaneous production of cello-oligosaccharide and glucose mono-decanoate from lignocellulose.

Enzymatic Synthesis of Glucose Monodecanoate in a Hydrophobic Deep Eutectic Solvent.

Environmentally friendly and biodegradable reaction media are an important part of a sustainable glycolipid production in the transition to green chemistry. Deep eutectic solvents (DESs) are an ecofriendly alternative to organic solvents. So far, only hydrophilic DESs were considered for enzymatic glycolipid synthesis. In this study, a hydrophobic DES consisting of (-)-menthol and decanoic acid is presented for the first time as an alternative to hydrophilic DES. The yields in the newly introduced hydrophobic DES are significantly higher than in hydrophilic DESs. Different reaction parameters were investigated to optimize the synthesis further. Twenty milligrams per milliliter iCalB and 0.5 M glucose resulted in the highest initial reaction velocity for the esterification reaction, while the highest initial reaction velocity was achieved with 1.5 M glucose in the transesterification reaction. The enzyme was proven to be reusable for at least five cycles without significant loss of activity.

4D Biofabrication of fibrous artificial nerve graft for neuron regeneration.

In this paper, we describe the application of the 4D biofabrication approach for the fabrication of artificial nerve graft. Bilayer scaffolds consisting of uniaxially aligned polycaprolactone-poly(glycerol sebacate) (PCL-PGS) and randomly aligned methacrylated hyaluronic acid (HA-MA) fibers were fabricated using electrospinning and further used for the culture of PC-12 neuron cells. Tubular structures form instantly after immersion of fibrous bilayer in an aqueous buffer and the diameter of obtained tubes can be controlled by changing bilayer parameters such as the thickness of each layer, overall bilayer thickness, and medium counterion concentration. Designed scaffolds showed a self-folded scroll-like structure with high stability after four weeks of real-time degradation. The significance of this research is in the fabrication of tuneable tubular nerve guide conduits that can simplify the current existing clinical treatment of neural injuries.