Regenerez : A Next-Generation Material for Functional Bioresorbable Coatings. by Carissa Smoot and Jeremy Harris, Ph.D, Secant Medical, Inc.

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1 Regenerez : A Next-Generation Material for Functional Bioresorbable Coatings by Carissa Smoot and Jeremy Harris, Ph.D, Secant Medical, Inc.

2 Coatings consisting of natural and synthetic origin play an important role in the world of medical devices both from a functional and a biological perspective. Collagen and similar materials are often used to coat surgical meshes to minimize the formation of intra-abdominal adhesions following hernia repair procedures. Coatings are also applied to cardiovascular grafts to provide a blood-tight structure until the graft is populated with host tissue. A coating made from a material that provides a beneficial mechanical and biological response would be an invaluable asset to medical device engineers. Regenerez, a bioelastomer made with poly(glycerol sebacate) (PGS) has shown tremendous promise in the field of tissue engineering and regenerative medicine, and it is an ideal coatings candidate due to its elastomeric and cell-friendly properties. 1,2 Coating Textiles To determine the coating properties of PGS, a variety of polymer-based textile structures were used as substrates for coating trials. In order for PGS to adhere to the polymer, the surface energy of the substrate must be greater than the surface energy (tension) of the coating liquid. Common materials used in biomedical textiles include polyethylene terephthalate (PET), polyglycolic acid (PGA), polyetheretherketone (PEEK) and polypropylene (PP). These materials have a wide range of surface energies (mn/m) PET (44.6), PGA (49.6), and PEEK (42.1) and are theoretically sufficient enough to allow wetting by PGS, which has surface energy of 42mN/m. 3,4 However, materials such as PP (30.1) and PE (35.7) will have a decreased affinity for PGS. These polymers will likely require surface modification and a potentially more advanced coating process. 3 The coating of the textile substrates was monitored using scanning electron microscopy (SEM), and the effect on mechanical properties was determined by measuring changes in tensile strength. The method used to coat the higher surface energy materials (i.e., PET, PEEK and PGA) is a standard solvent-based dip-coating process. The micrographs in Figure 1 depict samples of PEEK, PGA and PET that were successfully coated using this process. A casting method can also be used on these polymers to create a film of PGS that encompasses the entire textile structure.

3 A B C D E F Figure 1. Representative SEM images comparing uncoated (A) PEEK, (B) PGA and (C) PET textiles to coated (D) PEEK, (E) PGA and (F) PET textiles. The coating solution consisted of 20% PGS in ethyl acetate. The dip-coating and casting methods afford the ability to create films from the micron to the millimeter scale. Whereas the casting method can only be controlled by the amount of PGS casted, the dip-coat method can regulate coating thickness in multiple ways. One way to control coating thickness is through the use of varying concentrations of PGS in the dip coating solution. To illustrate the effect of dip-coating concentration, three samples of PET knit mesh were coated with a solution of 10%, 20% and 30% PGS. A B C Figure 2. Representative SEM images of PET knit mesh dip-coated with a (A) 10%, (B) 20% and (C) 30% solution of PGS in ethyl acetate.

4 In Figure 2, the 10% PGS solution shows minimal PGS coating, while the 20% coating shows the PGS beginning to bind the multifilament structure together. At 30%, the PGS coating is thick enough to essentially create a monofilament structure out of the multifilament yarn. In some cases, increasing the percent solids in the coating solution is not the optimal method for increasing PGS film thickness. Another method for building coating thickness is by depositing multiple layers of PGS (see Figure 3). This can be achieved by dip coating for a short period of time, allowing the solvent to evaporate, and re-dipping for the same amount of time. This process can be repeated with each layer to create a thicker PGS coating. The use of a higher percent solids coating solution with the layering process will result in a faster build-up of PGS than a lower percent solids solution. This is a useful method to evenly increase coating thickness without increasing the percentage of PGS in the coating solution. A B C D E Figure 3. Representative SEM images of a PET woven fabric coated with (A) 1 layer, (B) 2 layers, (C) 3 layers, (D) 4 layers and (E) 5 layers of 20% PGS in ethyl acetate. Another method for controlling coating thickness is increasing the dip time in the coating solution. The effect of increasing dip time to increase coating thickness is most pronounced at higher PGS concentrations. Figure 4 shows the effect of using four different dip times including 5 seconds, 2 minutes, 5 minutes and 10 minutes. The SEM images demonstrate that longer dip

5 A B C D E Figure 4. Representative SEM images of (A) uncoated PET woven fabric and (B) PET woven fabric coated with a 30% PGS in ethyl acetate solution for 5 seconds, (C) 2 minutes, (D) 5 minutes and (E) 10 minutes. times result in increased coating thickness, which is indicated by the increased coverage of the PET yarn filaments. To form the elastomeric version of PGS, the resulting film must first be cured to impart the desired level of elasticity. As the coating thickness is varied by the methods described above, the resulting cure time also varies. For example, a longer dip time with a higher concentration of PGS will take longer to cure than one layer deposited from a dilute solution of PGS. Therefore the elasticity of the PGS-coated textile can be tailored by changing cure time. Longer cure times result in a stiffer coating, whereas the minimum cure time produces a more viscoelastic coating. Samples of PET coated in a 30% PGS in ethyl acetate solution were cured in a vacuum oven at 120 C for 3, 4, 6, 9, 10 and 13 days. Figure 5 depicts the trend of decreasing crystallization temperature with increasing cure times, signifying an increase in PGS crosslink density.

6 Peak Load (N) Crystallization Temperature ( C) Cure Time (Days) Figure 5. Graph of DSC crystallization temperature as a function of cure time. Strength and Strain Testing Tensile strength and torsional strain are two parameters used to investigate the mechanical effect imparted by the PGS coating on the textile structures. Tensile tests were performed on samples of uncoated and coated PET woven fabric and PET knitted mesh. Both of the coated samples were dip-coated using a 30% PGS in ethyl acetate solution for 1 minute. In addition, torsional testing was completed on uncoated and coated PET woven ribbon samples prepared under the same conditions as the tensile tested samples. The tensile testing was used to monitor the effect of the PGS coating on the maximum peak load of the textile Uncoated PET Woven Coated PET Woven Uncoated PET Knitted Coated PET Knitted Table 1. Peak load data from the tensile testing system for uncoated and coated PET textiles.

7 The peak load that an uncoated textile structure experiences before breaking will vary depending on its method of construction (see Table 1). However, both structures show an increased peak load when coated with PGS. The PET woven fabric shows roughly an 80% increase in peak load when coated with PGS, and the PET knit mesh shows an approximate 20% increase. The varied effect of the PGS coatings indicates that the peak load increase from the PGS coating is dependent on the textile construct, because both samples were coated under the same conditions but resulted in a different peak load increase. In addition to the increase in peak load of the two PET samples, the failure mechanism also changed when the textile was coated with PGS. The stress-strain curve of the uncoated samples exhibits a saw tooth pattern as the individual filaments break prior to failure. However, the coated samples exhibited no fluctuation prior to failure. Break Line Figure 6. Representative SEM images of failure point of uncoated PET woven fabric after tensile testing. Break Line Figure 7. Representative SEM images of failure point of coated PET woven fabric after tensile testing.

8 Modulus (Pa) SEM images of the uncoated PET woven fabric following tensile testing show that the area of the break is frayed and jagged (see Figure 6). The images of the break point of the coated PET woven fabric show a clean, even break (see Figure 7) as a result of the PGS binding the multifilament structure into a larger, stronger monofilament structure. Instead of the individual filaments bearing the load separately, the PGS enables the filaments to work together, dispersing the tensile load over a larger area. The increase in peak load with the PGS coating suggests the PET textile has increased stiffness, however, torsional testing indicates the PGS coating imparts elasticity to the textile. Using a rheometer fitted with a torsional testing apparatus, amplitude sweeps can be performed on samples with largely solid character. Amplitude sweeps measure storage modulus (solid character) and loss modulus (liquid character) as a function of strain. In this case, the term strain refers to the ratio of the deflection path of the tool to the distance between the two tools, or the sample height. The test is conducted by securing a strip of uncoated or coated textile between two clamps and oscillating to achieve the appropriate percentage of strain. Figure 8 depicts an amplitude sweep taken on an uncoated and 30% PGS coated sample of PET woven ribbon. 1.0E E E E E E Strain (%) Figure 8. Amplitude sweep of uncoated (blue) and PGS coated (red) PET woven ribbon. Triangles and squares represent G (loss modulus) and G (storage modulus), respectively.

9 Modulus (Pa) The higher storage and loss modulus values for the uncoated woven ribbon indicate the sample is more stiff and rigid compared to the coated sample. For the coated sample, the lower storage and loss modulus values signify that the PGS coating creates more of a flexible, viscoelastic material. The amplitude sweep of a thermoset PGS sample (Figure 9) shows the linearity of the modulus values over the same strains, much like the response observed in Figure 8 of the coated PET woven ribbon. This result supports the concept that the PGS coating is responsible for the rheological response of the coated textile. 1.0E E E Strain (%) Figure 9. Amplitude sweep of thermoset PGS. Triangles and squares represent G (loss modulus) and G (storage modulus), respectively. In addition, the amplitude sweep data in Figure 8 illustrates the ability of PGS to better maintain the structure of the textile, similar to the effects seen in the tensile testing of the coated sample. This occurrence is shown in the increase of storage and loss modulus around 0.5% strain in the uncoated sample, but not in the coated sample. This event occurs due to the crinkling or the disruption of the uncoated textile structure (see Figure 10).

10 C D A B Figure 10. Images of (A) coated PET woven ribbon, (B) uncoated PET woven ribbon, (C) uncoated PET woven fabric and (D) coated PET woven fabric after torison testing. The image of the woven fabric sample in Figure 10 (C and D) shows an uncoated and coated sample that was subjected to an even larger amount of strain than the PET woven ribbon described in Figure 10 (A and B). Consequently, the difference between these two uncoated samples is more drastic, but the coated samples maintain their structure in both examples. Furthermore, the decrease in modulus values seen at higher strains is indicative of the sample reaching its yield strain, or the point in which the structure begins to break down. In the amplitude sweep of the uncoated and coated PET woven ribbon, the storage modulus values of the coated samples remain more linear to higher strain values than the uncoated sample, further supporting that PGS helps to better maintain the textile s integrity. In Vitro Degradation Results In order to investigate the degradation behavior of PGS as a coating, a degradation study of PGS-coated PET woven fabric was conducted. A series of samples with increasing PGS film thicknesses were prepared to more specifically see how coating thickness affects degradation rate. Varied coating thicknesses were achieved with a 10% PGS coating solution, a 20% solution and a 30% solution using three different dip times, and a thick film sample achieved by the neat method. The graph in Figure 11 depicts the average PGS coating masses for each film thickness.

11 Coating Mass (mg) % 30% 5 sec 30% 5 min 30% 10 min Thick Film Figure 11. Average PGS coating mass values for each film thickness. Eight samples of each coating thickness were prepared to remove one sample at eight different time points. The samples were placed in sterilized petri dishes and soaked in 0.5 M PBS (ph=7.4) in an incubator set at 37.0 C. At the designated time point, the samples were rinsed and dried until a constant mass was obtained. Each sample was then observed by SEM to determine changes in surface morphology due to degradation. Mass loss values for each of the samples over a two-week period are shown in Table 2. The percent mass loss at each time point is fairly consistent for the 20% and 30% samples, regardless of dip time. The thick film sample lost less PGS during Week 1, which can be explained by surface area. The dip-coated samples have a thin film of PGS that conformally coats the individual filaments, resulting in a larger surface area. The thick film is a solid block of PGS, resulting in a smaller amount of exposed surface area. Sample % Mass Loss Week 1 % Mass Loss Week 2 20% % 5 sec % 5 min % 10 min Thick Film 6.86 No Sample Removed Table 2. Degradation Mass Loss Results at Week 1 and Week 2

12 Although not by a large amount, the percent mass loss in Week 2 is slightly higher for most of the degradation samples. One of the advantages of PGS over other resorbable biomaterials is that PGS undergoes surface erosion as opposed to bulk erosion during degradation. Figure 12 shows that the surface erosion mechanism holds even when PGS is used as a coating. A B C Figure 12. Representative SEM images of PET woven fabric. These images show only a small portion of the sample, but this observation was observed throughout the entire sample. (A) uncoated, (B) 30% 10-minute coated after 1 week degradation and (C) 30% 10-minute coated after 2 weeks degradation The SEM micrographs show the emergence of the underlying filaments of the weave structure and more of the top-layer filaments, indicating that the PGS coating is degrading. Future studies to further investigate the degradation profile of PGS on PET will include FTIR microscope analysis. Conclusion As the demand for performance and biocompatibility in medical devices continues to increase, so will the need for devices that are more biologically and physically compliant. Coatings technology provides a bolt-on technology for materials commonly used in medical devices, as they have already have shown utility in improving the biological and physical properties of finished devices. As a coating, PGS has tremendous potential based on its ability to uniformly coat multiple polymeric materials in a controlled and reproducible manner. The PGS coating enhanced the mechanical properties of the coated textile by increasing the maximum tensile load and elasticity of the construct. Early degradation study results show that the PGS coating is degrading through a surface erosion mechanism that is consistent with other studies. Future work includes continued degradation studies and determining release kinetics of drug-loaded PGS coatings.

13 References 1. Wang, Y., Ameer, G.A., Sheppard, B.J., and Langer, R. (2002). A tough biodegradable elastomer. Nature Biotechnology 20(6), Rai, R., Tallawi, M., Grigore, A., Boccaccini, A.R. (2012) Synthesis, properties and biomedical applications of poly(glycerol sebacate) (PGS): a review. Progress in Polymer Science 37(8), Solid surface energy data (SFE) for common polymers. Retrieved from: 4. Rai, R. et. al. (2013). Materials Science and Engineering C33, Jeremy Harris, Ph.D., is technical director at Secant Medical, Inc., and Carissa Smoot is a scientist at the company.

14 2014 Secant Medical, Inc. The information contained herein is subject to change without notice. Secant Medical shall not be liable for technical or editorial errors or omissions contained herein. 700 W. Park Ave. Perkasie, PA t f