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Biodegradable, Elastic Shape-Memory Polymers for Potential Biomedical Applications

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Science  31 May 2002:
Vol. 296, Issue 5573, pp. 1673-1676
DOI: 10.1126/science.1066102

Abstract

The introduction of biodegradable implant materials as well as minimally invasive surgical procedures in medicine has substantially improved health care within the past few decades. This report describes a group of degradable thermoplastic polymers that are able to change their shape after an increase in temperature. Their shape-memory capability enables bulky implants to be placed in the body through small incisions or to perform complex mechanical deformations automatically. A smart degradable suture was created to illustrate the potential of these shape-memory thermoplastics in biomedical applications.

Current approaches for implanting medical devices, many of which are polymeric in nature, often require complex surgery followed by device implantation. With the advent of minimally invasive surgery (1), it is possible to place small devices with laprascopes. Such advances create new opportunities but also new challenges. How does one implant a bulky device or knot a suture in a confined space? It occurred to us that the creation of biocompatible (and ideally in many cases degradable) shape-memory polymers with the appropriate mechanical properties might enable the development of novel types of medical devices.

Shape-memory polymers possess the ability to memorize a permanent shape that can substantially differ from their initial temporary shape. Large bulky devices could thus potentially be introduced into the body in a compressed temporary shape by means of minimally invasive surgery and then be expanded on demand to their permanent shape to fit as required. In the same way, a complex mechanical deformation could be performed automatically instead of manually by the surgeon. The transition from the temporary to the permanent shape could be initiated by an external stimulus such as a temperature increase above the switching transition temperatureT trans of the polymer [movie S1 (19)].

The thermally induced shape-memory effect has been described for different material classes: polymers (2, 3), such as polyurethanes (4–7), poly(styrene-block-butadiene) (8) and polynorbornene (9, 10); hydrogels (11,12); metallic alloys (13); and ceramics (14). All of these materials are nondegradable in physiological environments and many lack either biocompatibility or compliance in mechanical properties.

In metallic alloys, the shape-memory effect is due to a martensitic phase transition (13). In contrast, the polymers designed to exhibit a thermally induced shape-memory effect require two components on the molecular level: cross-links to determine the permanent shape and switching segments withT trans to fix the temporary shape. AboveT trans, the permanent shape can be deformed by application of an external stress. After cooling belowT trans and subsequent release of the external stress, the temporary shape is obtained. The sample recovers its permanent shape upon heating to T >T trans.

Cross-links can be either covalent bonds or physical interactions. Recently, we have reported on shape-memory polymers (15), which are covalently cross-linked polymer networks containing hydrolyzable switching segments. Emphasis in the present work was put on the development of a group of polymers that contain physical cross-links. These thermoplastics are easily processed from solution or melt and are substantially tougher than polymer networks. In particular, they are degradable, showing linear mass loss during hydrolytic degradation.

We selected linear, phase-segregated multiblockcopolymers as the structural concept for our polymer system, because this polymer architecture allows tailoring of macroscopic properties by variation of molecular parameters.

In the first step of the polymer synthesis, macrodiols with different thermal characteristics are synthesized through ring-opening polymerization of cyclic diesters or lactones, with a low-molecular-weight diol as initiator, and purified (16). In the current study, oligo(ɛ-caprolactone)diol (OCL) was chosen as the precursor for the switching segments having a melting transition temperature (T m). Crystallizable oligo(p-dioxanone)diol (ODX), with a higherT m than OCL was chosen as a hard segment to provide the physical cross-links (17). The melting transition of the latter macrodiols is determined by the average chain length, which can be tailored by the monomer/initiator ratio (16, 17).

In the second step, the two macrodiols are coupled with 2,2(4),4-trimethylhexanediisocyanate (18). Hard segment contents of the synthesized polymers range from 0 to 83 weight % (wt %); and number-average molecular weights (M n), which were determined by means of gel permeation chromatography relative to polystyrene standards, are between 35,000 and 77,000, with polydispersities around 2. Figure 1 shows melting properties of multiblockcopolymers differing in their hard segment contents. Glass transition temperatures are between –51° and 0°C [table S2 (19)].

Figure 1

Tm and enthalpies ΔHm of multiblockcopolymers (36).Tm (OCL), solid squares; ΔHm (OCL), solid circles;Tm (ODX), open squares; ΔHm (ODX), open circles.

The multiblockcopolymers can be elongated up to 1000% [table S1 (19)] before they break. This allows deformations between permanent and temporary shape up to 400%, whereas the maximum deformation for Ni-Ti alloys is 8% (20). The mechanical properties strongly depend on the hard segment content. Increasing the amount of ODX in the reaction mixture leads to a stiffer polymer and a decrease of the corresponding elongations at break. This can be observed at all three investigated temperatures and is due to increased crystallinity [table S1 (19)].

To quantify shape-memory properties, programming and recovery were investigated by cyclic thermomechanical tests (21, 22). This simple test describes shape memory in one dimension; however, the effect takes place in all three dimensions. The effect is commonly described with two important parameters. The strain fixity rate R f describes the ability of the switching segment to fix the mechanical deformation, which is applied during the programming process. For our polymers,R f lies between 98 and 99.5%. The strain recovery rate R r quantifies the ability of the material to recover its permanent shape. R rdepends on the cycle number and gradually approaches 100% because of reorientation of the polymer chains in the unoriented pressed films during the early cycles, because of inelastic behavior. In the first cycle, R r has values between 76 and 80% for our multiblockcopolymers and reaches 98 to 99% in the third cycle. Ni-Ti alloys show stresses in the range of 200 to 400 MPa during shape-memory transition, whereas the shape-memory thermoplastics produce stresses in the range between 1 and 3 MPa, depending on the hard segment content (23). The lower value for shape-memory polymers resembles the mechanical stresses in soft tissue (24).

To record the change in elongation during the shape-memory effect, another cyclic thermomechanical experiment was performed (Fig. 2). Step 1 is the deformation of the permanent shape and corresponds to a standard stress-strain test. After maintaining this strain for 5 min to allow relaxation for chains, the stress is then held constant while the sample is cooled (step 2), whereby the temporary shape is fixed. Then stress is completely removed after waiting for 10 min (step 3), and the sample is now in its temporary shape. Heating in step 4 (2 K min−1) actuates the shape-memory effect. The contraction of the sample can be observed on the strain axis, and the fastest shape change is recorded atT trans = 40°C.

Figure 2

Cyclic thermomechanical experiment of PDC35 (37) with T trans = 40°C. Results of the first cycle are shown. Step 1 of the experiment was strain-controlled; steps 2 through 4 to the beginning of next cycle were stress-controlled.

We introduced hydrolyzable ester bonds in our polymers so that they would cleave under physiological conditions. The degradation kinetics can be controlled through the composition and relative mass content of the precursor macrodiols. An increase in the ODX content leads to a faster loss in mass (Fig. 3), because the concentration of rapidly hydrolyzable ODX-ester bonds in the amorphous phase is increased.

Figure 3

Hydrolytic degradation of thermoplastic shape-memory elastomers in aqueous buffer solution (pH 7) at 37°C. The relative mass loss for multiblockcopolymers differing in their hard segment content is shown (PDC10, circles; PDC17, squares; PDC31, upward-pointing triangles; PDC42, downward-pointing triangles). m(t), Sample mass after a degradation period t; m(t 0), original sample mass.

Established synthetic degradable suture materials are mainly aliphatic polyhydroxy acids showing bulk degradation. This degradation process can be split into several stages (25), the first three of which are swelling, loss of molecular weight, and loss of sample mass.

The degradation of l-lactide–based polyesters shows a nonlinear mass loss leading to a sudden release of potentially acidic degradation products from the bulk material, which may cause a strong inflammatory response (26). The high crystallinity of oligomer particles slows down degradation at the end of the process and leads to the formation of fibrous capsules in vivo (27). In contrast, the multiblockcopolymers presented here show linear mass loss in vitro (Fig. 3), resulting in a continuous release of degradation products.

The tissue compatibility of our polymer was investigated with chorioallantoic membrane (CAM) tests, which are a sensitive method of evaluating toxicity (28). Nine separate experiments were carried out. All tests showed good tissue compatibility when graded according to Folkman (29). There was no detectable change in the number or shape of blood vessels or damage under or in the vicinity of the polymer film (Fig. 4).

Figure 4

Results of CAM tests of PDC38 (sample length: left, ∼0.3 cm; right, ∼0.5 cm). For a positive control sample, see (25).

A challenge in endoscopic surgery is the tying of a knot with instruments and sutures to close an incision or open lumen. It is especially difficult to manipulate the suture so that the wound lips are pressed together under the right stress. When the knot is fixed with a force that is too strong, necrosis of the surrounding tissue can occur (30). If the force is too weak, scar tissue, which has poorer mechanical properties, forms and may lead to the formation of hernias (31). A possible solution is the design of a smart surgical suture, whose temporary shape would be obtained by elongating the fiber with controlled stress. This suture could be applied loosely in its temporary shape; when the temperature was raised aboveT trans, the suture would shrink and tighten the knot, applying the optimum force (32) (Fig. 5).

Figure 5

A fiber of a thermoplastic shape-memory polymer was programmed by stretching about 200%. After forming a loose knot, both ends of the suture were fixed. The photo series shows, from top to bottom, how the knot tightened in 20 s when heated to 40°C. This experiment is also available as movie S2 (19).

An additional set of experiments to test the feasibility of this concept was performed. The highly elastic shape-memory thermoplastics were extruded into monofilaments (33). A sterilized suture (34) was programmed under sterile conditions by exerting a controlled stress on the extruded fiber and subsequent thermal quenching. This smart suture was tested in the following animal model: A rat (WAG; weight, 250 g; albino) was killed and shaved. An incision was made through the belly tissue and the abdominal muscle. The wound was loosely sutured with a standard surgical needle (Hermann Butsch, size 15, Embedded Image circle). When the temperature was increased to 41°C, the shape-memory effect was actuated (Fig. 6). This test was carried out four times using two different animals. For these tests, the fibers were elongated by 200% during programming and were able to generate a force of 1.6 N upon actuation of the shape-memory effect in vitro. During the animal experiment, 0.1 N could be detected in the surrounding tissue (35).

Figure 6

Degradable shape-memory suture for wound closure. The photo series from the animal experiment shows (left to right) the shrinkage of the fiber while temperature increases.

This feasibility study suggests that this type of material has the potential to influence how implants are designed and could enable new surgical devices in the future.

  • * To whom correspondence should be addressed. E-mail: a.lendlein{at}mnemoscience.de

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