Fully Biodegradable Elastomer-Based Device for Oral Macromolecule Delivery.

Oral devices, such as foil-type devices, show great potential for the delivery of poorly permeable macromolecules by enabling unidirectional release of the loaded pharmaceutical composition in close proximity to the epithelium in the small intestine or colon. However, one of the primary concerns associated with the use of foil-type devices so far has been the utilization of nonbiodegradable elastomers in the fabrication of the devices. Therefore, research into biodegradable substitute materials with similar characteristics enables drug delivery in a sustainable and environmentally friendly manner. In this study, a biodegradable elastomer, polyoctanediol citrate (POC), was synthesized via a one-pot reaction, with subsequent purification and microscale pattern replication via casting. The microstructure geometry was designed to enable fabrication of foil-type devices with the selected elastomer, which has a high intrinsic surface free energy. The final elastomer was demonstrated to have an elastic modulus ranging up to 2.2 ± 0.1 MPa, with strain at failure up to 110.1 ± 1.5%. Devices were loaded with acetaminophen and enterically coated, demonstrating 100% release at 2.5 h, following dissolution for 1 h in 0.1 M hydrochloric acid and 1.5 h in pH 6.8 phosphate-buffered saline. The elastomer demonstrated promising properties based on mechanical testing, surface free energy evaluation, and degradation studies.

Transformation of metallo-elastomer grafts in a carotid artery interposition model over a year.

Current vascular grafts, primarily Gore-Tex® and Dacron®, don't integrate with the host and have low patency in small-diameter vessels (<6 mm). Biomaterials that possess appropriate viscoelasticity, compliance, and high biocompatibility are essential for their application in small blood vessels. We have developed metal ion crosslinked poly(propanediol-co-(hydroxyphenyl methylene)amino-propanediol sebacate) (M-PAS), a biodegradable elastomer with a wide range of mechanical properties. We call these materials metallo-elastomers. An initial test on Zn-, Fe-, and Cu-PAS grafts reveals that Cu-PAS is the most suitable because of its excellent elastic recoil and well-balanced polymer degradation/tissue regeneration rate. Here we report host remodeling of Cu-PAS vascular grafts in rats over one year. 76 % of the grafts remain patent and >90 % of the synthetic polymer is degraded by 12 months. Extensive cell infiltration leads to a positive host remodeling. The remodeled grafts feature a fully endothelialized lumen. Circumferentially organized smooth muscle cells, elastin fibers, and widespread mature collagen give the neoarteries mechanical properties similar to native arteries. Proteomic analysis further reveals the presence of important vascular proteins in the neoarteries. Evidence suggests that Cu-PAS is a promising material for engineering small blood vessels.

Highly Elastic, Bioresorbable Polymeric Materials for Stretchable, Transient Electronic Systems.

Substrates or encapsulants in soft and stretchable formats are key components for transient, bioresorbable electronic systems; however, elastomeric polymers with desired mechanical and biochemical properties are very limited compared to non-transient counterparts. Here, we introduce a bioresorbable elastomer, poly(glycolide-co-ε-caprolactone) (PGCL), that contains excellent material properties including high elongation-at-break (< 1300%), resilience and toughness, and tunable dissolution behaviors. Exploitation of PGCLs as polymer matrices, in combination with conducing polymers, yields stretchable, conductive composites for degradable interconnects, sensors, and actuators, which can reliably function under external strains. Integration of device components with wireless modules demonstrates elastic, transient electronic suture system with on-demand drug delivery for rapid recovery of post-surgical wounds in soft, time-dynamic tissues.

Soft, Long-Lived, Bioresorbable Electronic Surgical Mesh with Wireless Pressure Monitor and On-Demand Drug Delivery.

Current research in the area of surgical mesh implants is somewhat limited to traditional designs and synthesis of various mesh materials, whereas meshes with multiple functions may be an effective approach to address long-standing challenges including postoperative complications. Herein, a bioresorbable electronic surgical mesh is presented that offers high mechanical strength over extended timeframes, wireless post-operative pressure monitoring, and on-demand drug delivery for the restoration of tissue structure and function. The study of materials and mesh layouts provides a wide range of tunability of mechanical and biochemical properties. Dissolvable dielectric composite with porous structure in a pyramidal shape enhances sensitivity of a wireless capacitive pressure sensor, and resistive microheaters integrated with inductive coils provide thermo-responsive drug delivery system for an antibacterial agent. In vivo evaluations demonstrate reliable, long-lived operation, and effective treatment for abdominal hernia defects, by clear evidence of suppressed complications such as adhesion formation and infections.

Micropatterned Elastomeric Composites for Encapsulation of Transient Electronics.

Although biodegradable, transient electronic devices must dissolve or decompose via environmental factors, an effective waterproofing or encapsulation system is essential for reliable, durable operation for a desired period of time. Existing protection approaches use multiple or alternate layers of electrically inactive organic/inorganic elements combined with polymers; however, their high mechanical stiffness is not suitable for soft, time-dynamic biological tissues/skins/organs. Here, we introduce a stretchable, bioresorbable encapsulant using nanoparticle-incorporated elastomeric composites with modifications of surface morphology. Nature-inspired micropatterns reduce the diffusion area for water molecules, and embedded nanoparticles impede water permeation, which synergistically enhances the water-barrier performance. Empirical and theoretical evaluations validate the encapsulation mechanisms under strains. Demonstration of a soft, degradable shield with an optical component under a biological solution highlights the potential applicability of the proposed encapsulation strategy.

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.

Controlled release of bioactive IL-2 from visible light photocured biodegradable elastomers for cancer immunotherapy applications.

Biodegradable elastomeric controlled-release poly (decane-co-tricarballylate) (PDET) based matrices capable of maintaining the stability and bioactivity of Interleukin-2 (IL-2) through the utilization of visible-light curing and solvent-free loading of the cytokine are reported. The elastomeric devices were fabricated by intimately mixing lyophilized IL-2 powder with the acrylated prepolymer before photocrosslinking. The bioactivity of the released protein was assessed by its ability to stimulate the proliferation of the C57BL/6 mouse cytotoxic T lymphocyte, and its concentration was analysed using ELISA. The influence of changes in the polymer's physicochemical and mechanical properties on IL-2 release kinetics and bioactivity were also studied. The increase in the device's surface area and the incorporation of trehalose in the loaded lyophilized mix increased the IL-2 release rate with drug release proceeding via typical zero-order release kinetics. Moreover, the decrease in the degree of acrylation of the prepared devices increased the IL-2 release rate. The bioactivity assay showed that IL-2 retained over 94% of its initial bioactivity throughout 28 days of the release period. A new protein delivery vehicle composed of biodegradable PDET elastomers was demonstrated to be promising and effective for linear, constant, and sustained osmotic-driven release of bioactive IL-2 and other sensitive proteins and hormones.

Optimized Synthesis of Biodegradable Elastomer PEGylated Poly(glycerol sebacate) and Their Biomedical Application.

Poly(glycerol sebacate) (PGS), a biodegradable elastomer, has been extensively explored in biomedical applications for its favorable mechanical properties and biocompatibility. Efforts have been made to fabricate multifunctional PGS copolymer in recent years, in particular PGS-co-PEG (poly(glycerol sebacate)-co-polyethylene glycol) polymers. However, rare research has been systematically conducted on the effect of reactant ratios on physicochemical properties and biocompatibility of PGS copolymer till now. In this study, a serial of PEGylated PGS (PEGS) with PEG content from 20% to 40% and carboxyl to hydroxyl from 0.67 to 2 were synthesized by thermal curing process. The effects of various PEGS on the mechanical strength and biological activity were further compared and optimized. The results showed that the PEGS elastomers around 20PEGS-1.0C/H and 40PEGS-1.5C/H exhibited the desirable hydrophilicity, degradation behaviors, mechanical properties and cell viability. Subsequently, the potential applications of the 20PEGS-1.0C/H and 40PEGS-1.5C/H in bone repair scaffold and vascular reconstruction were investigated and the results showed that 20PEGS-1.0C/H and 40PEGS-1.5C/H could significantly improve the mechanical strength for the calcium phosphate scaffolds and exhibited preferable molding capability for fabrication of the vascular substitute. These results confirmed that the optimized PEGS elastomers should be promising multifunctional substrates in biomedical applications.

Synthesis, characterization & cytocompatibility of poly (diol-co-tricarballylate) based thermally crosslinked elastomers for drug delivery & tissue engineering applications.

The aim of this study was to investigate the synthesis and in vitro characterization of thermoset biodegradable poly (diol-co-tricarballylate) (PDT) elastomeric polymers for the purpose of their use in implantable drug delivery and tissue engineering applications. The synthesis was based on thermal crosslinking technique via a polycondensation reaction of tricarballylic acid with aliphatic diols of varying chain lengths (C6-C12). PDT prepolymers were synthesized at 140 °C for 20 min. After purification, the prepolymers were molded and kept at 120 °C for 18 h under vacuum to complete the crosslinking process. PDT prepolymers were characterized by DSC, FT-IR, 1H NMR and GPC. The PDT elastomers were also subjected to thermal and structural analysis, as well as sol content, mechanical testing, in vitro degradation and cytocompatibility studies. The mechanical properties and sol content were found to be dependent on synthesis conditions and can be controlled by manipulating the crosslinking density and number of methylene groups in the chain of precursor aliphatic diol. The family of thermally crosslinked PDT biodegradable polyesters were successfully prepared and characterized; besides they have promising use in drug delivery and other biomedical tissue engineering applications.

Additive manufactured biodegradable poly(glycerol sebacate methacrylate) nerve guidance conduits.

Entubulating devices to repair peripheral nerve injuries are limited in their effectiveness particularly for critical gap injuries. Current clinically used nerve guidance conduits are often simple tubes, far stiffer than that of the native tissue. This study assesses the use of poly(glycerol sebacate methacrylate) (PGSm), a photocurable formulation of the soft biodegradable material, PGS, for peripheral nerve repair. The material was synthesized, the degradation rate and mechanical properties of material were assessed and nerve guidance conduits were structured via stereolithography. In vitro cell studies confirmed PGSm as a supporting substrate for both neuronal and glial cell growth. Ex vivo studies highlight the ability of the cells from a dissociated dorsal root ganglion to grow out and align along the internal topographical grooves of printed nerve guide conduits. In vivo results in a mouse common fibular nerve injury model show regeneration of axons through the PGSm conduit into the distal stump after 21 days. After conduit repair levels of spinal cord glial activation (an indicator for neuropathic pain development) were equivalent to those seen following graft repair. In conclusion, results indicate that PGSm can be structured via additive manufacturing into functional NGCs. This study opens the route of personalized conduit manufacture for nerve injury repair. STATEMENT OF SIGNIFICANCE: This study describes the use of photocurable of Poly(Glycerol Sebacate) (PGS) for light-based additive manufacturing of Nerve Guidance Conduits (NGCs). PGS is a promising flexible biomaterial for soft tissue engineering, and in particular for nerve repair. Its mechanical properties and degradation rate are within the desirable range for use in neuronal applications. The nerve regeneration supported by the PGS NGCs is similar to an autologous nerve transplant, the current gold standard. A second assessment of regeneration is the activation of glial cells within the spinal cord of the tested animals which reveals no significant increase in neuropathic pain by using the NGCs. This study highlights the successful use of a biodegradable additive manufactured NGC for peripheral nerve repair.

Biocompatible, degradable thermoplastic polyurethane based on polycaprolactone-block-polytetrahydrofuran-block-polycaprolactone copolymers for soft tissue engineering.

Biodegradable synthetic polymers have been widely used as tissue engineering scaffold materials. Even though they have shown excellent biocompatibility, they have failed to resemble the low stiffness and high elasticity of soft tissues because of the presence of massive rigid ester bonds. Herein, we synthesized a new thermoplastic polyurethane elastomer (CTC-PU(BET)) using poly ester ether triblock copolymer (polycaprolactone-block-polytetrahydrofuran-block-polycaprolactone triblock copolymer, PCTC) as the soft segment, aliphatic diisocyanate (hexamethylene diisocyanate, HDI) as the hard segment, and degradable diol (bis(2-hydroxyethyl) terephthalate, BET) as the chain extender. PCTC inhibited crystallization and reduced the melting temperature of CTC-PU(BET), and BET dramatically enhanced the thermal decomposition and hydrolytic degradation rate when compared with conventional polyester-based biodegradable TPUs. The CTC-PU(BET) synthesized in this study possessed a low tensile modulus and tensile strength of 2.2 MPa and 1.3 MPa, respectively, and an elongation-at-break over 700%. Meanwhile, it maintained a 95.3% recovery rate and 90% resilience over ten cycles of loading and unloading. In addition, the TPU could be electrospun into both random and aligned fibrous scaffolds consisting of major microfibers and nanobranches. 3T3 fibroblast cell culture confirmed that these scaffolds outperformed the conventional biodegradable TPU scaffolds in terms of substrate-cellular interactions and cell proliferation. Considering the advantages of this TPU, such as ease of synthesis, low cost, low stiffness, high elasticity, controllable degradation rate, ease of processability, and excellent biocompatibility, it has great prospects to be used as a tissue engineering scaffold material for soft tissue regeneration.

Biodegradation and biocompatibility of haloarchaea-produced poly(3-hydroxybutyrate-co-3-hydroxyvalerate) copolymers.

We previously reported that the tailor-made random poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (R-PHBHV) and higher-order PHBHV (O-PHBHV) produced by haloarchaea possessed unique material properties to meet biomedical application-specific requirements. Here, we further investigated the biocompatibility and biodegradation of these novel materials. Cell biocompatibility of solution-cast films, assessed using rat fibroblast and osteoblast cells, revealed that R-PHBHV and O-PHBHV exhibited better support for cell attachment and proliferation compared with the bacteria-produced poly-3-hydroxybutyrate (PHB) and PHBHV or polylactic acid (PLA). In vitro and in vivo biodegradation of these materials were evaluated in lipase-containing phosphate buffered solution (LPBS) at pH 7.4 and by implantation in the rabbit dorsal subcutis, respectively. As expected, the R-PHBHV and O-PHBHV films degraded much faster in vivo than those observed in vitro, as demonstrated by obvious weight loss, heavy surface erosion, and fast molecular weight drop under implantation condition. These films showed diverse in vivo degradation rates. Among them, the O-PHBHV-1 film degraded fastest and even faster than PLA. Generally, the tissue response was mild for R-PHBHV and O-PHBHV compared with the controls during the implantation period. Taken together, these data revealed that R-PHBHV and O-PHBHV copolyesters had a wild range of biodegradation profiles and excellent biocompatibility. Thus, haloarchaea-produced PHBHV materials would have great potential for use in different biomedical applications.

Controlled Release of Small Molecules from Elastomers for Reducing Epidermal Downgrowth in Percutaneous Devices.

The elevated infection rise associated with indwelling devices can compromise the performance of percutaneous devices and increase the risk of complications. High infection rates are associated with both the high bacterial load on the skin and epidermal downgrowth at the interface of the indwelling material. Here, we propose a drug-eluting material that promotes local dermal regeneration to reduce epidermal downgrowth. Mesoporous elastomeric matrices composed of naturally occurring monomers were prepared by a combination of photo- and thermal-crosslinking. Elastomeric devices loaded with conjugated linoleic acids (CLA), a class of small molecules that promote local anti-inflammatory responses, can deliver these compounds for 7 d (DCLA-elastomer = 3.94 × 10-9 cm2/s, 95% CI [3.12 × 10-9, 4.61 × 10-9]). In a mouse model, CLA-eluting elastomeric matrices increase the M2 population (5.0 × 103 ± 1.4 × 103 cells/cm2), compared to blank devices (3.8 × 103 ± 2.2 × 103 cells/cm2), and also reduce skin contraction (98.9 ± 6.4%), compared to blank devices (70.9 ± 9.3%) at 7 d. Dermal downgrowth is also attenuated at 14 d (60.4 ± 32.4 µm) compared to blank devices (171.7 ± 93.8 µm). CLA-eluting elastomers are therefore a viable strategy to reduce epidermal downgrowth in percutaneous devices.

Robust and biodegradable elastomers based on corn starch and polydimethylsiloxane (PDMS).

Designing starch-based biopolymers and biodegradable composites with durable mechanical properties and good resistance to water is still a challenging task. Although thermoplastic (destructured) starch has emerged as an alternative to petroleum-based polymers, its poor dimensional stability under humid and dry conditions extensively hinders its use as the biopolymer of choice in many applications. Unmodified starch granules, on the other hand, suffer from incompatibility, poor dispersion, and phase separation issues when compounded into other thermoplastics above a concentration level of 5%. Herein, we present a facile biodegradable elastomer preparation method by incorporating large amounts of unmodified corn starch, exceeding 80% by volume, in acetoxy-polyorganosiloxane thermosets to produce mechanically robust, hydrophobic bioelastomers. The naturally adsorbed moisture on the surface of starch enables autocatalytic rapid hydrolysis of polyorganosiloxane to form Si-O-Si networks. Depending on the amount of starch granules, the mechanical properties of the bioelastomers can be easily tuned with high elastic recovery rates. Moreover, starch granules considerably lowered the surface friction coefficient of the polyorganosiloxane network. Stress relaxation measurements indicated that the bioelastomers have strain energy dissipation factors that are lower than those of conventional rubbers, rendering them as promising green substitutes for plastic mechanical energy dampeners. Corn starch granules also have excellent compatibility with addition-cured polysiloxane chemistry that is used extensively in microfabrication. Regardless of the starch concentration, all of the developed bioelastomers have hydrophobic surfaces with lower friction coefficients and much less water uptake capacity than those of thermoplastic starch. The bioelastomers are biocompatible and are estimated to biodegrade in Mediterranean seawater within three to six years.

Biodegradable elastomers for biomedical applications and regenerative medicine.

Synthetic biodegradable polymers are of great value for the preparation of implants that are required to reside only temporarily in the body. The use of biodegradable polymers obviates the need for a second surgery to remove the implant, which is the case when a nondegradable implant is used. After implantation in the body, biomedical devices may be subjected to degradation and erosion. Understanding the mechanisms of these processes is essential for the development of biomedical devices or implants with a specific function, for example, scaffolds for tissue-engineering applications. For the engineering and regeneration of soft tissues (e.g., blood vessels, cardiac muscle and peripheral nerves), biodegradable polymers are needed that are flexible and elastic. The scaffolds prepared from these polymers should have tuneable degradation properties and should perform well under long-term cyclic deformation conditions. The required polymers, which are either physically or chemically crosslinked biodegradable elastomers, are reviewed in this article.

Fabrication and characterization of biomimetic multichanneled crosslinked-urethane-doped polyester tissue engineered nerve guides.

Biomimetic scaffolds that replicate the native architecture and mechanical properties of target tissues have been recently shown to be a very promising strategy to guide cellular growth and facilitate tissue regeneration. In this study, porous, soft, and elastic crosslinked urethane-doped polyester (CUPE) tissue engineered nerve guides were fabricated with multiple longitudinally oriented channels and an external non-porous sheath to mimic the native endoneurial microtubular and epineurium structure, respectively. The fabrication technique described herein is highly adaptable and allows for fine control over the resulting nerve guide architecture in terms of channel number, channel diameter, porosity, and mechanical properties. Biomimetic multichanneled CUPE guides were fabricated with various channel numbers and displayed an ultimate peak stress of 1.38 ± 0.22 MPa with a corresponding elongation at break of 122.76 ± 42.17%, which were comparable to that of native nerve tissue. The CUPE nerve guides were also evaluated in vivo for the repair of a 1 cm rat sciatic nerve defect. Although histological evaluations revealed collapse of the inner structure from CUPE TENGs, the CUPE nerve guides displayed fiber populations and densities comparable with nerve autograft controls after 8 weeks of implantation. These studies are the first report of a CUPE-based biomimetic multichanneled nerve guide and warrant future studies towards optimization of the channel geometry for use in neural tissue engineering.

Development of Photocrosslinkable Urethane-Doped Polyester Elastomers for Soft Tissue Engineering.

Finding an ideal biomaterial with the proper mechanical properties and biocompatibility has been of intense focus in the field of soft tissue engineering. This paper reports on the synthesis and characterization of a novel crosslinked urethane-doped polyester elastomer (CUPOMC), which was synthesized by reacting a previously developed photocrosslinkable poly (octamethylene maleate citrate) (POMC) prepolymers (pre-POMC) with 1,6-hexamethylene diisocyanate (HDI) followed by thermo- or photo-crosslinking polymerization. The mechanical properties of the CUPOMCs can be tuned by controlling the molar ratios of pre-POMC monomers, and the ratio between the prepolymer and HDI. CUPOMCs can be crosslinked into a 3D network through polycondensation or free radical polymerization reactions. The tensile strength and elongation at break of CUPOMC synthesized under the known conditions range from 0.73±0.12MPa to 10.91±0.64MPa and from 72.91±9.09% to 300.41±21.99% respectively. Preliminary biocompatibility tests demonstrated that CUPOMCs support cell adhesion and proliferation. Unlike the pre-polymers of other crosslinked elastomers, CUPOMC pre-polymers possess great processability demonstrated by scaffold fabrication via a thermally induced phase separation method. The dual crosslinking methods for CUPOMC pre-polymers should enhance the versatile processability of the CUPOMC used in various conditions. Development of CUPOMC should expand the choices of available biodegradable elastomers for various biomedical applications such as soft tissue engineering.