New minimally-invasive implants for diagnosis, therapy and regenerative medicine

Concept of syringe-injectable, self-expandable and ultra-conformable magnetic ultrathin films (MNP-SMP nanosheets) composed of polyurethane-based shape-memory polymer and magnetic nanoparticles.

Ultrathin films are able to be injected using minimally-invasive syringe needles and can be used as a platform to deliver molecular and cellular drugs. The use of shape-memory polymer also enables unprecedented temperature-dependent control to allow for adhesion and removal of the nanosheets on biological surfaces.

Syringe-injectable biomaterials, medical devices and engineered tissues have attracted great attention as minimally-invasive implants for diagnosis, therapy and regenerative medicine. Free-standing polymeric ultrathin films, commonly referred to as polymeric nanosheets, are one of the commonly used platforms for syringe-injectable biomedical devices because of their flexibility and conformability.

These nanosheets are less than 1 micrometer in thickness, which is thinner than a strand of hair that is usually about 100 micrometers wide. They are a promising platform for drug delivery through needle-injection. Despite recent development in nanosheets technologies using polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA), polymeric nanosheets are yet to overcome several technical challenges to serve as an effective injectable platform: namely, (1) limitation in the size of nanosheets injectable through medical needles, (2) suboptimal mechanical robustness (e.g., ripping during injection), and (3) limited control over shape recovery and motion control after injection.

To overcome these limitations, researchers from Digital Manufacturing and Design (DManD) Centre at the Singapore University of Technology and Design (SUTD) developed nanosheets using polyurethane-based shape-memory polymer (SMP) and magnetic nanoparticles (MNP) to demonstrate unprecedented capabilities to handle nanosheets. SMP offers two unique mechanical characteristics – a large change in the Young’s moduli by the change in temperature, and shape-memory effect (SME) to recover the memorised shape.

In addition, the researchers demonstrated that the fabricated SMP nanosheets can be rendered magnetic with MNP to perform non-contact motion control using an external magnetic field. Specifically, the following four capabilities were demonstrated by using the 710 nm thick nanosheet with the glass transition temperature (Tg) of 25?C: (1) syringe-injectability through the medical needles, (2) self-expandability after ejection, (3) conformability and removability on the biological surfaces, and (4) guidability in an external magnetic field. These capabilities enable in vivo practical applications as a syringe-injectable platform.

As an added advantage, the change of the modulus by temperature offers a unique capability to control the adhesion and removal of the MNP-SMP nanosheet on the biological surfaces. This would have been difficult to achieve using conventional nanosheets having a constant modulus and has not been demonstrated previously.

Envisaging the syringe-injectable delivery of molecular drugs or cellular constructs into internal organs, the researchers added the MNP-SMP nanosheets with an additional layer of PLGA, which is best known as a biomaterial used for drug delivery, to extend the functionality as a carrier of molecular and cellular drugs. This can be done without compromising the demonstrated capabilities. SMP and MNP offered the same capabilities to the nanosheets containing an additional layer of PLGA, suggesting the vast potential of the developed nanosheets for drug and cell delivery.

“The MNP-SMP nanosheets can be further functionalized by loading or printing drugs, cells and electric circuits on the surface by integrating emerging printing technologies such as inkjet printing, 3D printing and bioprinting,” said Dr Kento Yamagishi from SUTD, the lead author of the paper.

“The MNP-SMP nanosheets will contribute to the development of advanced syringe-injectable medical devices as a platform to deliver drugs and cells to the specific site or lesion in the body for minimally invasive diagnosis and therapy,” added Principal Investigator, Assistant Professor Michinao Hashimoto from SUTD.

Learn more: SUTD develops syringe-injectable, self-expandable and ultraconformable magnetic nanosheets for smart drug delivery

 

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A new smart material that could have major implications for health care

Professor James H. Henderson and Ph.D. candidate Shelby L. Buffington

Researchers in the College of Engineering and Computer Science have developed a material—a new kind of shape memory polymer (SMP)—that could have major implications for health care.

SMPs are soft, rubbery, “smart” materials that can change shape in response to external stimuli like temperature changes or exposure to light. They can hold each shape indefinitely and turn back when triggered to do so.

SMPs have many potential biomedical applications. For example, they are ideal as cardiovascular stents because they can be one shape for surgical insertion and another once positioned in a blood vessel. The warmth of the patient’s body is all that is required to trigger the shape change.

Along with collaborators at Bucknell University, Syracuse University researchers have designed an SMP that can change its shape in response to exposure to enzymes and is compatible with living cells. It requires no additional trigger, such as a change in temperature. Given these properties, it can respond to cellular activity like healing.

“The enzymatic sensitivity of the material allows it to respond directly to cell behavior,” explains biomedical engineering Ph.D. candidate Shelby L. Buffington. “For instance, you could place it over a wound, and as the tissue remodeled and degraded it, the SMP would slowly pull the wound closed. It could be adapted to play a role in treating infections and cancer by adjusting the material’s chemistry.”

The research team includes Buffington, Justine E. Paul ’18, bioengineering junior Mark M. Macios, Professor James H. Henderson and Bucknell’s Patrick T. Mather and Matthew M. Ali Ph.D. ’18. Their research, “Enzymatically triggered shape memory polymers,” was published in Acta Biomaterialia in January.

The team created the material using a process called dual electrospinning, in which a high-voltage current is applied to two needle tips pumping two separate polymer solutions. The voltage draws out the polymer fibers, and they are blended into a fiber polymer mat. The proper combination of fibers gives the material its shape memory qualities.

Detailed in their paper, the teams analyzed the material’s properties, shape memory performance and cytocompatibility. Their experiments successfully demonstrated that the SMP’s original shape could be recovered through a degree of reversal, or degradation, of the shape-fixing phase.

Today, the research team is examining their SMP in cancer and macrophage cell cultures. They hope that with additional research, they will uncover practical uses for their material using lower concentrations of enzymes, produced by less extreme cellular activity.

“We anticipate that the materials we’re developing could have broad application in health care. For example, our SMPs could be used in drugs that only activate when the target cells or organ are in the desired physiological state, in scaffolds that guide tissue regeneration in response to the behavior of the regenerating tissue itself, and in decision-making biosensors that guide patient treatment more effectively,” Henderson says. “We’re very excited to have achieved these first enzymatically responsive SMPs.”

Learn more: New Material Developed at Syracuse University is a Biomedical Breakthrough

 

 

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4D Printing: Going beyond 3D printing to add a new dimension for additive manufacturing

via LLNL

via LLNL

A team of Lawrence Livermore National Laboratory researchers has demonstrated the 3D printing of shape-shifting structures that can fold or unfold to reshape themselves when exposed to heat or electricity. The micro-architected structures were fabricated from a conductive, environmentally responsive polymer ink developed at the Lab.

In an article published recently by the journal Scientific Reports, Lab scientists and engineers revealed a strategy for creating boxes, spirals and spheres from shape memory polymers (SMPs), bio-based “smart” materials that exhibit shape-changes when resistively heated or when exposed to the appropriate temperature.

Lab researcher Jennifer Rodriguez examines a 3D printed box that was “programmed” to fold and unfold when heated
While the approach of using responsive materials in 3D printing, often known as “4D printing,” is not new, LLNL researchers are the first to combine the process of 3D printing and subsequent folding (via origami methods) with conductive smart materials to build complex structures.

In the paper, the researchers describe creating primary shapes from an ink made from soybean oil, additional co-polymers and carbon nanofibers, and “programming” them into a temporary shape at an engineered temperature, determined by chemical composition. Then the shape-morphing effect was induced by ambient heat or by heating the material with an electrical current, which reverts the part’s temporary shape back to its original shape.

Through a direct-ink writing 3D printing process, LLNL researchers produced several types of structures, including a stent that expanded after being exposed to heat.
“It’s like baking a cake,” said lead author Jennifer Rodriguez, a postdoc in LLNL’s Materials Engineering Division. “You take the part out of the oven before it’s done and set the permanent structure of the part by folding or twisting after an initial gelling of the polymer.”

Ultimately, Rodriguez said, researchers can use the materials to create extremely complex parts.

“If we printed a part out of multiple versions of these formulations, with different transition temperatures, and run it through a heating ramp, they would expand in a segmented fashion and unpack into something much more complex,” she said.

Through a direct-ink writing 3D printing process, the team produced several types of structures — a bent conductive device that morphed to a straight device when exposed to an electric current or heat, a collapsed stent that expanded after being exposed to heat and boxes that either opened or closed when heated.

“We have these materials with 3D structures but they have extra smart properties; they can retain a memory of the previous structure,” said Lab staff scientist James Lewicki. “It opens up a whole new property set. If you can print with these polymer composites you can build things and electrically activate them to unfold. Instead of a dumb lump, you are left with this sentient, responsive material.”

The research derives from a Laboratory Directed Research & Developmentproject to develop high-performance 3D-printed carbon fiber composites.

Others contributing to the paper were Lab scientists and engineers Cheng Zhu, Eric Duoss, Thomas Wilson and Chris Spadaccini.

Learn more: Going beyond 3D printing to add a new dimension for additive manufacturing

 

 

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Shape Shifters: Demonstrating Tunable Phase Shifting

Image courtesy of Paul Chaikin, NYU A liquid mixture solidifies to different solid phases upon cooling (left) and heating (right). At low temperature, colloidal spherical particles form crystals due to pressure from collisions with the surrounding polymer. At high temperature, the polymer sticks to and bridges the particles, forming a random aggregate. At the crossing point (an intermediate temperature shown in the center), a liquid dispersion is formed because the attractive forces compensate for the collisions.

Image courtesy of Paul Chaikin, NYU
A liquid mixture solidifies to different solid phases upon cooling (left) and heating (right). At low temperature, colloidal spherical particles form crystals due to pressure from collisions with the surrounding polymer. At high temperature, the polymer sticks to and bridges the particles, forming a random aggregate. At the crossing point (an intermediate temperature shown in the center), a liquid dispersion is formed because the attractive forces compensate for the collisions.

Reversible self-assembled structures balance two competing attractions to enable stimuli-responsive materials.

The Science

Scientists devised a new approach that balances attractions between particles and promises to become a useful tool to create designer materials that can repair damage. The discovery of a cross point between temperature-dependent interactions between particles – not previously thought possible – opens the doors for more nimble synthesis. The crosspoint exploits the temperature-dependent behavior (solubility and adsorption) of a polymer. Researchers discovered that a liquid polymer-colloid mixture on cooling and heating forms different solid phases reversibly. These solids are formed by two distinct pathways: (1) at low temperature, pressure from collisions with the surrounding non-adsorbing polymer forms a colloidal crystal and (2) at high temperature, the polymer sticks (adsorbs) to particles, forming a random aggregate.

The Impact

This research opens a new pathway to stimuli-responsive self-assembled structures. Using the crosspoint pathway, it may now be possible to (1) thermally control viscoelastic properties, (2) heal defects that occur during assembly, (3) more controllably sequester and release objects, and (4) exert fine control over inter-particle interactions for sequential assembly of two- and three-dimensional materials with precisely organized optical and mechanical functions.

Summary

A new approach that balances attractions between particles promises to become a useful tool to fine-tune self-assembly and add functionality, such as error correction during assembly and damage repair. Previous polymer-directed routes for particle self-assembly were in stark contrast to biological systems that can form, reconfigure, and repair complex assemblies within cells by balancing assembly and disassembly processes.

In this research, understanding of the pathways for both assembly and disassembly was developed. The transformative aspect is the identification by researchers at New York University of a crossing point between the two pathways for a polymer-colloid mixture previously thought impossible; the crossing point mimics the biological assembly-disassembly capability. Adsorption properties of polymers change with temperature. At low temperature, colloidal crystals are formed due to pressure from collisions with surrounding non-adsorbing polymer. Actually, the colloids are squeezed together to increase the volume available to the non-adsorbing polymer. This mechanism for forming colloidal crystals was well known, but what was observed next was quite surprising. On heating, the colloidal crystal melted to form a liquid polymer-colloid mixture. Beyond this point, the solubility of the polymer decreased as the temperature increased; eventually, the polymer was able to weakly stick (adsorb) to the particles, creating bridges that solidify the liquid to a random aggregate gel.

At the crossover point between colloidal crystal deformation and gel formation, these new attractions (so-called enthalpic attraction, in thermodynamic terminology) completely balance the forces exerted by the volume available to the polymer from the particles being squeezed together (so-called entropic attraction). The crossing point depends on the change in solubility of the non-adsorbing polymer, resulting in a liquid-to-solid transition on cooling and heating. Most importantly, this process is thermally reversible at each stage of assembly and disassembly, which could allow entry into and out of the particles. As a result, it may be possible to heal defects in assembled structures, and to fabricate two- and three-dimensional materials with desired optical and mechanical properties. The general nature of these interactions suggests that they can be applied over a broad range of self-assembly approaches, such as the DNA-directed assembly of particle networks, to stimuli-responsive functional materials.

Read more: Shape Shifters: Demonstrating Tunable Phase Shifting

 

 

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Products that Reversibly Change Shape with Temperature May Revolutionize Medicine

Potential application for a copolymer network comprising reversible shape shifts caused by temperature variations between body and room temperature via www.hzg.de

Potential application for a copolymer network comprising reversible shape shifts caused by temperature variations between body and room temperature
via www.hzg.de

New research highlights the capability of reversible shape-memory polymers to change their shape when heated to body temperature and then switch back to their original shape when cooled to room temperature

The technology could have applications in temperature intervals relevant for biomedical applications—for example, devices for external short-term applications such as bandages or temporary fixation parts, where the product would be activated upon exposure to human body temperature. The technology could also be used for home-care products to support the daily life of disabled or elderly people or devices such as reversible self-locking shoe binders for handicapped people.

Read more: Products that Reversibly Change Shape with Temperature May Revolutionize Medicine

 

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