Neural Tissue Engineering, by Jonathan Hummel

Nerve Tissue Damage

Different responses to damage in the peripheral and central nervous system [1]

Central and peripheral nervous system [3]

Damage to nervous tissue in both the central (CNS) and peripheral (PNS) nervous system arises from a wide variety of causes. Direct mechanical trauma, inadequate blood supply, or failure of the cellular machinery of the neurons themselves can result in the severing of axons, damage of neuron cell bodies, or disruption of existing synapses.[1] While all three types of nerve tissue damage are interconnected, the repair of severed axons has historically received the most study, largely due to the fact that the prospects of recovery are much better in the absence of extensive cell body damage or synapse obstruction by aggregates.[1][2] Regardless of the initial cause, the response to axon damage by the local cells in neural tissues differ dramatically between the CNS and PNS, resulting in different challenges when developing treatments.[1] Glial cells, or more specifically Schwann cells, are the cells responsible for forming the myelin sheath that surrounds, protects, and nourishes the axons of neurons.[2] Shortly after the disruption of an axon in the PNS, macrophages are attracted to the area to swiftly remove the cellular debris of the Schwann cells, as well as any debris from the damaged axon itself. Damage of the axon triggers the cell body associated with that axon to express a variety of genes associated with the production of axon components as well as elongation. Surviving Schwann cells in the area proliferate and reorganize into a linear supporting structure. They also release growth factors and proteins that guide the direction in which the growth cone of the extending axon moves. This ensures that the extending axon moves toward the appropriate target neuron or tissue to repair communication.[1] In the CNS, the response to the exact same axon damage results in a different course of events that are much less favorable for tissue repair. The cellular debris are not cleaned up nearly as rapidly as they are in the PNS and persist for weeks, rather than days, which poses obstacles for axon extension and reformation of myelin structures. On top of that, expression of genes associated with axon repair rarely occurs in CNS neurons the way it does in the PNS. When axon extension is initiated by a CNS neuron, proper function of the growth cone is inhibited by factors released by oligodendrocytes, the CNS equivalent of the Schwann cells. Another type of glial cell, called astrocytes, release other factors in response to axon damage that inhibits the extension of the axon.[1] Thus, in the PNS there are mechanisms that actively promote the repair of damaged neural tissues, while in the CNS there are mechanisms in place to actively prevent the repair of neural tissues. The goal of neural tissue engineering is to restore lost neural tissue function by using engineered cells and/or materials. The strategies behind tissue engineering in CNS and PNS tissues are thus very different, and as one can imagine, there has been much more success in the PNS because preexisting repair mechanism simply need to be aided.[2] It should also be mentioned that other sources of nerve tissue damage, such as degenerative diseases like Alzheimer's, do not result in direct axon damage but a buildup of proteins and aggregates that impede proper neural function. Thus, approaches to treatment of these malfunctions are very different and further understanding of these disorders is required.[4]

Economic and Societal Impact

The exact costs associated with nerve tissue damage are difficult to estimate, largely due to the fact that there are such a wide variety of neurological disorders and traumas, some of which are not fully understood or are under the realm of psychology and/or psychiatry.[5] That being said, the costs both economically and emotionally that stem from nerve tissue damage are surely noteworthy. To get a sense for the economic impacts, one can look at the costs associated with any individual health issue related to nerve tissue damage or malfunction. For example, the overall annual cost of traumatic brain injuries in the United States is estimated to be $48.3 billion and the lifetime cost of caring for a traumatic brain injury survivor is estimated to be between $0.6 and $1.9 million.[6] The costs associated with degenerative diseases are even larger, with a projected $226 billion to be spent due to Alzheimer's in 2015.[7] Especially in the case of nerve tissue damage and disease, the emotional and quality of life impacts are just as important as the economic effects. Damage and degeneration of nerve tissues in the PNS often result in the pain, loss of feeling, and loss of control or function in the affected parts of the body.[8] These symptoms result in varying degrees of disability and loss of productivity in those affected, not to mention general discomfort.[5] In nerve tissue damage and degeneration that affects the CNS, the greatest losses are often in cognition and the ability to normally interact with family or friends. In the case of CNS degeneration, even before the more grave effects set in, there is often a level of fear and pain associated with the prospect of losing cognition or control, which also cannot be overlooked.[5] What is often most discouraging for those affected by neurological damage or degeneration is the lack of effective treatment to solve or combat these problems. This is largely due to a massive knowledge gap with regards to the nervous system and the specific causes of disorders and modes of repair.[2][5] While the field of neural tissue engineering is currently only able to address simple PNS damage, further study of tissue engineering in both the PNS and CNS could someday lead to solutions to even the most complex and detrimental neurological degenerative diseases.

Summary of Neural Tissue Engineering Progress

The following timeline is hardly an exhaustive list of the key events in the history of neural tissue engineering. It does, however, provide a general summary of the progression of this field over time:

• 1543-1627 : Gabriele Ferrara developed and described a procedure for connecting severed nerves with gentle sutures and limb immobilization.[2]
• 1954 : Use of autologous nerve graphs for peripheral nervous system repair, which was developed during WWII, is formally published as a method of repair.[2]
• 1972 : Methods of nerve repair are further improved with use of the operating microscope and understanding of the negative effects of suture tensions on nerve healing.[2]

Methods of Neural Tissue Repair

As described earlier, the mechanisms of response to damage in the CNS and PNS are dramatically different and thus the challenges are different when designing repair methods in each part of the nervous system.[2] While there is a long way to go in expanding the treatment options for both the CNS and PNS, there are currently many more methods of repair that have been developed to treat damage in the PNS:

In the Peripheral Nervous System

Various treatment strategies for nerve injuries in the peripheral nervous system [9]

Historically, the main way to treat damage of nerves in the PNS has been via various forms of nerve connecting surgery. These procedures started out with the direct suturing of larger disconnected nerves over short distances.[2][9] In the mid 20th century, the concept of nerve tissue grafting was introduced which greatly improved the recovery process, largely due to the fact that direct suturing causes tensions in nerve tissues that stunt the healing process.[2] Today, serious PNS damage is treated primarily with nerve tissue grafts and this method is generally accepted as the most reliable.[2] This is sure to change, however, as improvements in nerve grafting have stagnated and the technique does not work in many situations (i.e. certain sized nerves or over certain distances).[2][9] In the early 2000's and on there has been an explosion of research into the use of artificial or decellularized nerve conduits to guide nerve tissue regeneration. Many of these engineered nerve conduits have shown increased or equal efficacy to traditional nerve grafts and some have even gained FDA approval, however their use in patients is still not widespread.[9]

Grafts

Diagram of the type of PNS nerve bundle that grafting and suturing are used on [9]

While direct suturing of severed nerves is still used in cases where the nerve bundle is sufficiently large, the distance to span is sufficiently small, and tension enforced on the bundle is low, the most common method used is currently grafting.[9] Nerve grafting involves taking a nerve from another source that matches the damaged nerve in terms of size and structure and stitching the appropriate ends together to bridge the gap. While one outcome of a nerve graft is that the transplanted nerve provides a functional rout of neural communication between severed ends, the most important outcome is that the transplanted nerve provides a guide for the axonal end of the damaged nerve to repair itself in the right direction.[9] There are three main types of nerve grafts that each have their advantages and disadvantages:

• Autografts - These are nerve grafts using a transplant nerve taken from elsewhere within the patient being treated. This is the most commonly used type of nerve graft. The most positive feature of nerve autograft is the low risk of immune response to the transplanted nerve. This comes at a price, however, as the site where the nerve was taken from loses nerve function locally and the fact that two surgeries are needed in the patient puts more of a load on the patient during recovery. In autografts, nerves are most often taken from locations where loss of function will be least problematic, such as sensory nerves just below the skin.[9] The fact that nerves need to be taken from the patient with minimal loss of important function highly limits the size and type of nerve damage that autographs can successfully repair.[9]

• Allografts - These are nerve grafts taken from another donor of the same species. While this type of graft has the advantage of taking a load off of the patient's body, it introduces higher risk of immune response to the foreign tissue. Mot to mention that allografts, much like organ transplants, are highly limited by the amount of compatible donors available.[9]

• Xenografts - These are grafts taken from a donor of another species. The major advantage of this method is that eliminates some of the intrinsic limitations of the other two methods, such as the availability of donors or adequately sized transplant nerves. One study in the late 90's showed that xenografts to repair sciatic nerves in rabbits yielded recoveries as successful as those attained by allograft. The main limitation of this method is that as the donor tissue is less and less genetically similar to the target tissue, the risk of immune response increases. Unlike the other two methods, xenograft has not yet been used in human treatment [9]

Decellularized Conduits

The shortcomings of autografts, along with the fact that the potential gains of allografts and xenografts are overshadowed by immune response, that lead researchers to explore decellularized nerve conduits in the early to mid 2000's.[9]

Future Directions

Stuff goes in here...

References

• [1] Zhang, Lijie, Jerry Hu, and Kyriacos A. Athanasiou. “The Role of Tissue Engineering in Articular Cartilage Repair and Regeneration.” Critical reviews in biomedical engineering 37.1-2 (2009): 1–57. Print.

• [1] Recovery from Neural Injury

• [2] Peripheral nerve regeneration: Experimental strategies and future perspectives

• [3] CNS/PNS photo

• [4] Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein.

• [5] http://jnnp.bmj.com/content/63/suppl_1/S19.full

• [6] http://www.brainandspinalcord.org/recovery-traumatic-brain-injury/cost-traumatic-brain-injury/index.html

• [7] http://www.alz.org/facts/overview.asp

• [8] http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm

• [9] Peripheral nerve conduits: technology update