Scarcity of appropriate biomaterials and the complexity of biological milieu have posed a great challenge to regenerative medicine, particularly in the repair of sectioned or crushed sections of peripheral nerves. The gold standard for treating nerve lesions is the autograft in which patient’s own peripheral nerve is harvested, but in the recent years, decellularized autologous tissue grafting is becoming common in which conduits of biological origin are used. To overcome the donor compatibility issues, researchers have now turned to biomaterials for fabricating tissue-engineered nerve grafts. In this regard, the criteria that biomaterials must address include: biocompatibility, mechanical properties, and porosity. Several natural and synthetic biomaterial nerve conduits (NC) have been approved that meet these criteria2. The focus of this paper will be on one such synthetic material, known as poly(DL-lactide-ɛ-caprolactone) or PCL. It is used in an approved product, Neurolac, from a Dutch company, Polyganics. Neurolac is similar to autografts, but provides the benefits of a conduit6.
Advantages of PCL
Certain properties of PCL have made it indispensible in nerve tissue engineering applications: superior viscoelastic and rheological properties over several other resorbable polymers that makes PCL easy to manipulate into a wide range of scaffolds; inexpensive means of production as compared to other aliphatic polyesters; FDA-approval that indicates its safety10; and structural resistance and permeability that allow improved myelination2. The structures made from PCL include: nanospheres, nanofibers, foams, knitted textiles, and various forms of scaffolds10. In this regard, PCL/Neurolac is used to provide guidance and protection to the regenerated axons, and eliminates the need for autologous transplants. It is used in reconstructing discontinuity of up to 20 mm in the peripheral nerve. It prevents ingrowth of fibrous tissue into nerve gaps during regeneration of the nerve from proximal to distal nerve stump of transected nerve7.
Biocompatibility, Biodegradability and Bioresorption
PCL-NC has been shown to be non-immunogenic as opposed to the collagen based nerve tubes7. Neurolac is safe and has been successfully used within the human body2. It starts to degrade after several weeks, and its degradation is complete after a year3. The first study to evaluate the long-term bioresorption of PCL was published in 2004, when Jansen et al implanted PCL nerve guides for 16 months in rats. Authors found small fragments of the biomaterial on epineurial edges of regenerated nerve. This delineated secondary foreign body reaction. In 2009, Meek and Jansen reported that PCL (Neurolac) NC do not completely resorb after two years of implantation in rats. At that time, biomaterial was not found macroscopically, but biomaterial fragments were observable microscopically, and foreign body reactions were also observed against biomaterial fragments. Due to the ulcers and auto-mutilation at the surgery site after two years, combined sensory and motor nerve recovery in sciatic nerve (through Sciatic Function Index) could not be measured6.
Existing Challenges and Proposed Solutions
One of the greatest challenges in the field is that none of the approved biomaterial NCs provides complete functional recovery. Since natural biomaterials offer superior regeneration of nerves, a possible solution could be to use PCL-composites with natural materials in line with the study by Yu et al (2011). These researchers prepared collagen/PCL fibrous scaffold through electrospinning technique. In vitro analysis showed collagen/PCL meshes to promote Schwann cell elongation, adhesion, and proliferation, and in vivo study indicated NCs to support sciatic nerve regeneration through 8 mm gap in adult rats11. To enhance the benefits of the proposed PCL-composites, PCL may form the outer shell, while natural material may form the inner layer to allow improved migration of peripheral nerves through conduit.
Along similar lines, prospective clinical study should be conducted to compare PCL-NCs with collagen-based or other conduits. On one hand, tubular collagen matrix structure of FDA-approved collagen type 1-based NCs – such as NeuroFlex and NeuroMatrix – has made them more bioresorbable, but on the other hand, they have weaker mechanical properties. Moreover, comparison of different FDA-approved polymers in humans – for example, comparing the performance of PCL-based Neurolac versus poly glycolic acid (PGA)-based Neurotube – is also challenging. The tubular structure of PCL (Neurolac) as compared to the woven PGA mesh tube structure of Neurotube is the reason why PCL-NCs have lower rate of degradation and less mechanical stability than PGA-based NCs: thin-walled amorphous PCL tubes, with an average 170 μm wall-thickness, were found to collapse in vivo 26 weeks postoperatively9. The greater mechanical stability of PGA-based NCs comes with a price: according to Shin et al (2009), PGA-based NC performed poorer than PCL-based NC in treating segmental nerve defect in rats.
So, a better solution is to use PCL-composites with materials that offer greater mechanical strength or greater bioresorbability than to alter the structure of PCL-based NCs. A related strategy would be to use neurotrophic factors (that trigger nerve regeneration) with PCL-based polymers. The problem is the optimization of dose, release kinetics, and half-lives. To address that,
The time to retain the ‘initial’ mechanical properties (such as strength and mass) and the time to retain ‘sufficient’ mechanical properties (such as prevention from kinking or collapse) of PCL-NCs versus other NCs and composites must be examined. In any case, an advantage of using these commercial NCs is to prevent the use of functional nerve of the patient for autografts.
In conclusion, PCL has found applications in peripheral nerve tissue engineering, particularly in the form of NCs. Despite being clinically safe, there are several unanswered questions regarding their long-term resorption, side effects, and compatibility with other polymers and agents. The solutions to these questions include: detailed studies on animals with larger size of individual groups; and the use of PCL-composites and neurotrophic factors.
- Arslantunali, D., Dursun, T., Yucel, D., Hasirci, N., & Hasirci, V. (2014). Peripheral nerve conduits: Technology update. Medical Devices, 7, 405–424.
- Belanger, K., Dinis, T. M., Taourirt, S., Vidal, G., Kaplan, D. L., & Egles, C. (2016). Recent strategies in tissue engineering for guided peripheral nerve regeneration. Macromolecular Bioscience, 16(4), 472–481.
- Bertleff, M. J., Meek, M. F., & Nicolai, J. P. (2005). A prospective clinical evaluation of biodegradable neurolac nerve guides for sensory nerve repair in the hand. Journal of Hand Surgery, 30(3), 513–518.
- Carriel, V., Alaminos, M., Garzón, I., Campos, A., & Cornelissen, M. (2014). Tissue engineering of the peripheral nervous system. Expert Review of Neurotherapeutics, 14(3), 301–318.
- Jansen, K., Meek, M. F., van der Werff, J. F., van Wachem, P. B., & van Luyn, M. J. (2004). Long-term regeneration of the rat sciatic nerve through a biodegradable poly(DL-lactide-epsilon-caprolactone) nerve guide: Tissue reactions with focus on collagen III/IV reformation. Journal of Biomedical Materials Research, Part A, 69(2), 334–341.
- Meek, M. F., & Jansen, K. (2009). Two years after in vivo implantation of poly(DL-lactide-epsilon-caprolactone) nerve guides: Has the material finally resorbed? Journal of Biomedical Materials Research, Part A, 89(3), 734–738.
- Polyganics. (n.d.). Neurolac®. Retrieved from www.polyganics.com
- Shin, R. H., Friedrich, P. F., Crum, B. A., Bishop, A. T., & Shin, A. Y. (2009). Treatment of a segmental nerve defect in the rat with use of bioabsorbable synthetic nerve conduits: A comparison of commercially available conduits. Journal of Bone & Joint Surgery, 91(9), 2194–2204.
- Stang, F., Keilhoff, G., & Fansa, H. (2009). Biocompatibility of different nerve tubes. Materials, 2(4), 1480–1507.
- Woodruff, M. A., & Hutmacher, D. W. (2010). The return of a forgotten polymer – Polycaprolactone in the 21st century. Progress in Polymer Science, 35(10), 1217–1256.
- Yu, W., Zhao, W., Zhu, C., Zhang, X., Ye, D., Zhang, W.,…Zhang, Z. (2011). Sciatic nerve regeneration in rats by a promising electrospun collagen/poly(ε-caprolactone) nerve conduit with tailored degradation rate. BMC Neuroscience, 12, 68.