Author: Tilda Barliya PhD
Peripheral nerve lacerations are common injuries and often cause long lasting disability (1a) due to pain, paralyzed muscles and loss of adequate sensory feedback from the nerve receptors in the target organs such as skin, joints and muscles (1b).
Nerve injuries are common and typically affect young adults with the majority of injuries occur from trauma or complication of surgery. Traumatic injuries can occur due to stretch, crush, laceration (sharps or bone fragments), and ischemia, and are more frequent in wartime, i.e., blast exposure. Domestic or occupational accidents with glass, knifes of machinery may also occur.
Statistics show that peripheral nervous system (PNS) injuries were 87% from trauma and 12% due to surgery (one-third tumor related, two-thirds non– tumor related). Nerve injuries occurred 81% of the time in the upper extremities and 11% in the lower extremities, with the balance in other locations (4).
Injury to the PNS can range from severe, leading to major loss of function or intractable neuropathic pain, to mild, with some sensory and/or motor deficits affecting quality of life.
Functional recovery after nerve injury involves a complex series of steps, each of which may delay or impair the regenerative process. In cases involving any degree of nerve injury, it is useful initially to categorize these regenerative steps anatomically on a gross level. The sequence of regeneration may be divided into anatomical zones (4):
- the neuronal cell body
- the segment between the cell body and the injury site
- the injury site itself
- the distal segment between the injury site and the end organ
- the end organ itself
A delay in regeneration or unsuccessful regeneration may be attributed to pathological changes that impede normal reparative processes at one or more of these zones.
Nanotechnology for regenerative nerves: by Gunilla Elam
Repairing nerve defects with large gaps remains one of the most operative challenges for surgeons. Incomplete recovery from peripheral nerve injuries can produce a diversity of negative outcomes, including numbness, impairment of sensory or motor function, possibility of developing chronic pain, and devastating permanent disability.
In the past few years several techniques have been used to try and repair nerve defects and include:
- Nerve autograph
- Biological or polymeric nerve conduits (hollow nerve guidance conduits)
For example, When a direct repair of the two nerve ends is not possible, synthetic or biological nerve conduits are typically used for small nerve gaps of 1 cm or less. For extensive nerve damage over a few centimeters in length, the nerve autograft is the “gold standard” technique. The biggest challenges, however, are the limited number and length of available donor nerves, the additional surgery associated with donor site morbidity, and the few effective nerve graft alternatives.
Degeneration of the axonal segment in the distal nerve is an inevitable consequence of disconnection, yet the distal nerve support structure as well as the final target must maintain efficacy to guide and facilitate appropriate axonal regeneration. There is currently no clinical practice targeted at maintaining fidelity of the distal pathway/target, and only a small number of researchers are investigating ways to preserve the distal nerve segment, such as the use of electrical stimulation or localized drug delivery. Thus development of tissue-engineered nerve graft may be a better matched alternative (6,7,9).
The guidance conduit serves several important roles for nerve regeneration such as:
a) directing axonal sprouting from the regenerating nerve
b) protecting the regenerating nerve by restricting the infiltration of fibrous tissue
c) providing a pathway for diffusion of neurotropic and neurotophic factors
Early guidance conduits were primarily made of silicone due to its stability under physiological conditions, biocompatibility, flexibility as well as ease of processing into tubular structures. Although silicone conduits have proven reasonably successful as conduits for small gap lengths in animal models (<5 mm). The non-biodegradability of silicone conduits has limited its application as a strategy for long-term repair and recovery. Tubes also eventually become encapsulated with fibrous tissue, which leads to nerve compression, requiring additional surgical intervention to remove the tube. Another limiting factor with inert guidance conduits is that they provide little or no nerve regeneration for gap lengths over 10 mm in the PNS unless exogenous growth factors are used (6,7).
In animal studies, biodegradable nerve guidance conduits have provided a feasible alternative, preventing neuroma formation and infiltration of fibrous tissue. Biodegradable conduits have been fabricated from natural or synthetic materials such as collagen, chitosan and poly-L-lactic acid.
Nanostructured Scaffolds for Neural Tissue Engineering: Fabrication and Design
At the micro- and nanoscale, cells of the CNS/PNS reside within functional microenvironments consisting of physical structures including pores, ridges, and fibers that make up the extracellular matrix (ECM) and plasma membrane cell surfaces of closely apposed neighboring cells. Cell-cell and cell-matrix interactions contribute to the formation and function of this architecture, dictating signaling and maintenance roles in the adult tissue, based on a complex synergy between biophysical (e.g. contact-mediated signaling, synapse control), and biochemical factors (e.g. nutrient support and inflammatory protection). Neural tissue engineering scaffolds are aimed toward recapitulating some of the 3D biological signaling that is known to be involved in the maintenance of the PNS and CNS and to facilitate proliferation, migration and potentially differentiation during tissue repair (9).
Nanotechnology and tissue engineering are based on two main approaches:
- Electrospinning (top-down) - involves the production of a polymer filament using an electrostatic force. Electrospinning is a versatile technique that enables production of polymer fibers with diameters ranging from a few microns to tens of nanometers.
- Molecular self-assembly of peptides (bottom-up) - Molecular self-assembly is mediated by weak, non-covalent bonds, such as van der Waals forces, hydrogen bonds, ionic bonds, and hydrophobic interactions. Although these bonds are relatively weak, collectively they play a major role in the conformation of biological molecules found in nature.
Pfister et al (6) very nicely summarized the various polymeric fibers been used to achieve the goal of nerve regeneration, even in humans. These material include a wide array of polymers from silica to PLGA/PEG and Diblock copolypeptides.
Many of these approaches also enlist many trophic factors that have been investigated in nerve conduits
Currently there are three general biomaterial approaches for local factor delivery:
- Incorporation of factors into a conduit filler such as a hydrogel
- Designing a drug release system from the conduit biomaterial such as microspheres
- Immobilizing factors on the scaffold that are sensed in place or liberated upon matrix degradation.
Maeda et al had a creative approach to bridge larger gaps by using the combination of nerve grafts and open conduits in an alternating “stepping stone” assembly, which may perform better than an empty conduit alone (8).
Peripheral nerve repair is a growing field with substantial progress being made in more effective repairs. Nanotechnology and biomedical engineering have made significant contributions; from surgical instrumentation to the development of tissue engineered grafting substitutes. However, to date the field of neural tissue engineering has not progressed much past the conduit bridging of small gaps and has not come close to matching the autograf. Much more studies are needed to understand the cell behaviour that can promote cell survival, neurite outgrowth, appropriate re-innervation and consequently the functional recovery post PNS/CNS injuries. This is since understanding of the cellular response to the combination of these external cues within 3D architectures is limited at this stage.
1a. Jaquet JB, Luijsterburg AJ, Kalmijn S, Kuypers PD, Hofman A, Hovius SE. Median, ulnar, and combined median-ulnar nerve injuries:functional outcome and return to productivity. J Trauma 2001 51: 687-692. http://www.ncbi.nlm.nih.gov/pubmed/11586160
1b. Lundborg G, Rosen B. Hand function after nerve repair. Acta Physiol (Oxf) 2007 189: 207-217. http://www.ncbi.nlm.nih.gov/pubmed/17250571
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3. Albert Aguayo. Nerve regeneration revisited. Nature Reviews Neuroscience 7, 601 (August 2006).
4. Burnett MG and Zager EL. Pathophysiology of Peripheral Nerve Injury: A Brief Review. Neurosurg Focus. 2004;16(5) .
5. Dag Welin. Neuroprotection and axonal regeneration after peripheral nerve injury. MEDICAL DISSERTATIONS
Welin, D., Novikova, L.N., Wiberg, M., Kellerth, J-O. and Novikov, L.N. Survival and regeneration of cutaneous and muscular afferent neurons after peripheral nerve injury in adult rats. Experimental Brain Research, 186, 315-323, 2008.
6. Pfister BJ., Gordon T., Loverde JR., Kochar AS., Mackinnon SE and Cullen Dk. Biomedical Engineering Strategies for Peripheral Nerve Repair: Surgical Applications, State of the Art, and Future Challenges. Critical Reviews™ in Biomedical Engineering 2011, 39(2):81–124. http://www.med.upenn.edu/cullenlab/user_documents/2011Pfisteretal-PNIReviewArticleCritRevBME.pdf
7. Zhou K, Nisbet D, Thouas G, Bernard C and Forsythe J. Bio-nanotechnology Approaches to Neural Tissue Engineering. Intechopen. Com. http://cdn.intechopen.com/pdfs/9811/InTech-Bio_nanotechnology_approaches_to_neural_tissue_engineering.pdf
8. Maeda T, Mackinnon SE, Best TJ, Evans PJ, Hunter DA, Midha RT. Regeneration across ’stepping-stone’ nerve grafts. Brain Res. 1993;618(2):196–202. http://www.ncbi.nlm.nih.gov/pubmed/?term=Maeda+T+and+regeneration+across+stepping+stone
9. Sedaghati T., Yang SY., Mosahebi A., Alavijeh MS and Seifalian AM. Nerve regeneration with aid of nanotechnology and cellular engineering. Biotechnol Appl Biochem. 2011 Sep-Oct;58(5):288-300. http://www.ncbi.nlm.nih.gov/pubmed/21995532
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