Totally tubular: Polymer plumbing for tissue engineering

Original paper: Multilayer Tubes that Constrict, Dilate, and Curl in Response to Stimuli

Content review: Danny Seara
Style review: Arthur Michaut

Our bodies rely on many types of tube-shaped organs to transport blood, air, water, food, urine, and feces. These tubular organs are stimuli-responsive: they can constrict or dilate, secrete chemicals, or act as a selective barrier in response to biological signals. Developing synthetic versions of natural tissue structures that mimic biological responses is at the cutting edge of tissue engineering, synthetic organ development, and even soft robotics design. But what materials can be used to grow responsive tubes in the lab? Many of the fundamental building blocks of biological tissues are naturally occurring polymers. However, growing stimuli-responsive tissue mimics with these materials has not been achieved. Fortunately, many examples of biological tissue have similar properties to synthetic polymer hydrogels which are easy to make in the lab. Polymer hydrogels are made of interconnected networks of synthetic polymer chains, linked together by crosslinker molecules and swollen with water – kind of like a wet sponge as shown in Figure 1. However, many processes that are currently used to make tubes from hydrogels require specialized equipment, like coaxial printing which requires many different custom-made print heads to make different sized tubes. In addition, such techniques don’t easily produce branched tubes common in biological systems. Recently, a group of engineers designed a simple and elegant method to construct stimuli-responsive millimeter-scale biomimetic tubes using a simple patterning process.

Colorful cartoon schematic showing the stepwise process of polymerization from iniator, monomer, and crosslinker small molecule to crosslinked polymer chains to hydrogel materials.
Figure 1. Synthetic crosslinked polymer are made by combining initiator, monomer, and crosslinker molecules (a) and initiating a polymerization reaction (b). This results in the formation of polymer chains that are crosslinked by covalent bonds (c) to form very large network molecules (d). When these networks swell in water, they form hydrogels (e). Hydrogels can be engineered to have similar water-to-organic content and mechanical properties as biological tissue.

To make tube-like structures, the researchers first mold a cylindrical template using the biopolymer agar (a natural vegetable gelatin) and then infuse it with initiator molecules. To grow a polymer hydrogel around the template, the agar cylinder is suspended in a bath containing monomer and crosslinker molecules. Once activated, the initiator molecules can leak out and interact with the monomers and crosslinkers in the bath to polymerize a hydrogel sleeve around the template. The researchers also added xanthan gum to thicken the monomer bath so the template can be suspended and a structurally sound tube can be grown (no cracks, holes, or missing tube walls). Finally, the agar template is dissolved in hot water, leaving a synthetic hydrogel tube. Figure 2 shows a schematic of this “inside-out” polymerization process.

Colorful cartoon schematic showing the stepwise process to make polymer hydrogel tubes with two photographs showing the finished tubes.
Figure 2. The simple method to grow synthetic polymer hydrogel tubes around degradable agar templates is represented by this schematic. Scale bars represent 4 mm. Schematic design and images courtesy of the original article.

The researchers were able to fabricate tubes with different geometries and patterns, growing proof-of-concept mimics of naturally occurring biological tube structures. Changing the diameter of the template cylinder controlled the size of the lumen (inner diameter) of the tube. The researchers could vary the lumen by an order of magnitude, from 4.5 millimeters down to 0.6 millimeters. A 20-minute “inside-out” polymerization reaction produced tubes with ~1 millimeter thick tube walls. Increasing the concentration of initiator in the template or the polymerization reaction time produced thicker tube walls. Adding xanthan gum to the monomer bath modified its viscosity and allowed the researchers to spatially separate different monomer species in the bath from left to right or top to bottom. In this way they could create patterned hydrogel tubes, such as tubes with lateral patterns (rings around the tube) and longitudinal patterns (stripes along the tube walls), as shown in Figure 3. By designing different hydrogel tube patterns, the researchers were able to grow synthetic tubes that responded to different stimuli much like biological tubes respond to stimuli in living organisms. 

Colorful cartoon schematic showing the stepwise process to make polymer stimuli-responsive hydrogel tubes using a different stripe patterns.
Figure 3. Shape-changing synthetic hydrogel tubes are made using viscous patterned monomer baths to embed lateral patterns (a) or longitudinal patterns (b). Three types of hydrogels were used to make these patterns: (i) a hydrogel that is non-responsive to temperature- or pH-based stimuli; (ii) a hydrogel that responds to increased temperature by contracting (shrinking in volume); and (iii) a hydrogel that responds to pH change by expanding (growing in volume). Schematic design and images courtesy of the original article.

The researchers used monomers that form responsive polymers to pattern the tubes and achieve different tube responses. The laterally-patterned tubes constricted with temperature changes and dilated in response to chemical triggers, like pH change. The longitudinally-patterned tubes curled into loops with temperature change. These coils formed because the tube components responded differently to changes in temperature (one component expanded more than the other) which caused the tube to bend. The researchers were even able to make rudimentary branched systems where the branches from the main tube could be programmed for different stimuli-response properties. 

A really exciting aspect of this method is that it works at physiological conditions (room temperature, aqueous environments, etc.). This means cells or other bioactive materials can be incorporated during tube-making, which is advantageous for regenerative medicine. This work is a great example of translating the fundamental study of polymers and responsive materials into real world applications. It also suggests many new engineering questions: Can we make synthetic and responsive tube systems from biopolymer hydrogels (like collagen or cellulose)? Can we incorporate synthetic tubes into other soft materials like gels or colloids to make complex structures? Can synthetic tubes be designed as chemical reaction conduits or implantable biological sensors? Can soft robots use tube systems for autonomous motion? The industrious tube engineer might imagine designing a patterned multi-tube system to generate tube-shaped robots that can crawl or grab objects using coiling tube tentacles. Ultimately, this work helps set the trajectory of future research as we head towards our not-so-distant future full of engineered tubular organs and squishy robots.

Leave a Reply