Next Article in Journal
A Finite Element Model for Trigger Finger
Previous Article in Journal
Implant-Supported Prosthetic Therapy of an Edentulous Patient: Clinical and Technical Aspects
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Prosthesis
Volume 2
Issue 3
10.3390/prosthesis2030014
prosthesis-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

A Systematic Review of the Effectiveness of Cell-Based Therapy in Repairing Peripheral Nerve Gap Defects

by
Muhammad Sana Ullah Sahar
1,*,
Matthew Barton
2,3 and
Geoffrey Tansley
1
1
School of Engineering and Built Environment, Griffith University, Gold Coast QLD 4215, Australia
2
Menzies Health Institute Queensland, Griffith University, Gold Coast QLD 4215, Australia
3
Clem Jones Centre for Neurobiology and Stem Cell Therapies, Griffith University, Gold Coast QLD 4215, Australia
*
Author to whom correspondence should be addressed.
Prosthesis 2020, 2(3), 153-167; https://doi.org/10.3390/prosthesis2030014
Submission received: 4 May 2020 / Revised: 14 June 2020 / Accepted: 1 July 2020 / Published: 4 July 2020
Browse Figures
Versions Notes

Abstract

:
Nerve prostheses are widely utilized to reconstruct segmental (gap) defects in peripheral nerves as an alternative to nerve grafting. However, with increasing gap length, the effectiveness of a nerve prosthesis becomes sub-optimal, which subsequently has made repairing larger gaps in peripheral nerves a significant challenge in the field of regenerative medicine. Recently, the structure of nerve prostheses has been significantly revised, which interestingly, has provided a promising avenue for the housing and proliferation of supportive cells. In this systematic review, cell implantation in synthetic nerve prostheses to enhance the regenerative capability of an injured nerve with a focus on identifying the cell type and mode of cell delivery is discussed. Of interest are the studies employing supportive cells to bridge gaps greater than 10 mm without the aid of nerve growth factors. The results have shown that cell therapy in conjunction with nerve prostheses becomes inevitable and has dramatically boosted the ability of these prostheses to maintain sustainable nerve regeneration across larger gaps and helped to attain functional recovery, which is the ultimate goal. The statistical analysis supports the use of differentiated bone-marrow-derived mesenchymal stem cells suspended in oxygen-carrying hydrogels in chitosan prostheses for bridging gaps of up to 40 mm; however, based on the imperfect repair outcomes, nerve grafting should not yet be replaced altogether.

1. Introduction

The primary purpose of every nerve gap repair technique is to hold the transected nerve ends together to facilitate nerve continuity. Under the regime of surgical solutions for repairing completely transected peripheral nerves, microsurgical neurorrhaphy and nerve grafting are the most common techniques used in practice. However, the inherent shortcomings of these techniques which include nerve distortion, increased tension at the coaptation site, graft rejection, donor site morbidity, aberrant regeneration of axons, and unsatisfactory results has led to the development of neural prosthetic techniques [1]. The use of nerve prostheses to bridge irreducible large gaps in peripheral nerves is becoming popular nowadays due to their off-the-shelf availability in different shapes and sizes. Nerve prostheses, which are mainly synthesized from degradable biomaterials, are known to provide several benefits, such as enhanced nerve regeneration across smaller-to-medium-sized nerve defects (1 to 10 mm), mitigating scar tissue development, and preventing the leakage of intraneural fluid; however, the success rates become highly variable in gaps with greater lengths [2], where the proximal stump of the injured nerve remains unable to find its distal counterpart and regenerating fibers become aberrant. This results in the formation of neuroma and scar tissues, which further impede the regeneration process, lengthens the recovery period and thereby jeopardizes the repair quality. Thus, this dilemma has stressed the need to find alternate ways to support nerve regeneration.
With the recent advances in tissue engineering, supportive cells are being considered as potential candidates for speeding up the quasi-static rate of peripheral nerve regeneration. Nerve prostheses seeded with a variety of stem cells, such as skin-derived stem cells (SdSCs), adipose-derived stem cells (ADSCs), and bone-marrow-derived stem cells (BMdSCs), are being tested regarding bridging nerve defects to observe their respective efficacy in promoting nerve regeneration over larger gaps; however, the majority of the studies have reported the use of cell transplantation techniques in bridging non-critical-sized gaps, i.e., 10 mm or less. Arguably, these smaller gaps can be repaired by traditional nerve repair techniques, and thus the therapeutic effect of the cell therapy cannot be fully realized. Therefore, to acknowledge the true potential of supportive cells used in gap repairs, a systematic literature search was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, which resulted in the collection of 268 studies obtained from online research databases in the context of peripheral nerve gap management using neural prostheses (see Figure 1). A total of 21 studies were found eligible for inclusion in this systematic review (reported in Table 1), while the rest of the studies were excluded based on the following criteria:
(a)
Studies that employed a nerve crush injury model, gapless repair model, or in vitro model.
(b)
Studies that used non-synthetic or biological prostheses derived from nerves, muscles, or intestines.
(c)
Studies where the segmental defect was 10 mm or less (the threshold for the length of a nerve gap was taken as 10 mm because most of the studies used a peripheral nerve injury model in rodents, and due to higher nerve regeneration capacity in smaller animals, the true efficacy of a nerve repair cannot be revealed over shorter nerve defects).
(d)
Studies where nerve growth factors were applied either endo- or exogenously.

2. Scope of the Manuscript

The primary objective of this review was to appraise the efficacy of cell implantation in nerve prostheses to achieve successful nerve regeneration along with functional recovery across critical-sized defects (>10 mm) in peripheral nerves. The secondary objective was to make recommendations about prosthetic materials and the source of stem cells for developing an optimal and reliable therapeutic modality.

3. Effectiveness of Cell Therapy

A neural prosthetic technique is a process of encasing stumps of a transected nerve in a hollow conduit to create a favorable environment for regenerating axons. Fundamentally, a nerve prosthesis allows the proximal nerve stump to grow and orientate toward the distal nerve stump in a guided manner, and therefore, essentially provide a bridging scaffold for regenerating nerve fibers without necessitating graft material. Earlier, we highlighted the importance of developing biodegradable nerve prostheses from polyglycolic acid (PGA), chitosan, and collagen to support nerve regeneration across smaller-to-medium-sized nerve gap defects [24]; however, for larger gap defects, traditional prostheses consistently failed to maintain sustainable nerve regeneration and functional outcomes remained generally poor [25]. Although it is evident that nerve prostheses are being widely utilized to reconstruct nerve defects, no clinically available prostheses are known to promote nerve regeneration across larger gaps and guarantee full functional recovery; subsequently, this has made the reconstruction of larger nerve defects a significant clinical challenge.
Nerve regeneration has a multi-stage neural tissue repair process involving Wallerian degeneration, recruiting macrophages for sweeping up the axonal degradation products (myelin debris), the formation of Bünger bands by Schwann cells for axonal guiding, and finally, the regeneration of axons [26,27]. Schwann cells (SCs) are the key player in this repair process as they provide neurotrophic support to regenerating fibers by secreting several neurotrophic factors, such as brain- and glial-derived neurotrophic factor [28]. Schwann cells are also involved in the myelination of the regenerating axons [29], which facilitates their pathway toward the distal end [30], thereby improving nerve regeneration [31]; and hence their presence appears to be indispensable for sustainable nerve regeneration over longer segmental defects [32]. Therefore, at the injury site, Schwann cells aids the onset of healthy nerve regeneration, resulting in enhanced axonal regeneration [31], which expedites the repair process [33], and ultimately helps to attain functional recovery comparable to nerve grafting that is better than repair performed using prostheses alone [13,34].
Recently, nerve prostheses manufactured in various structural variations to mimic a nerve’s native intracellular matrix structure to provide a native nerve-like environment to regenerating axons are becoming popular. The structural variations mostly involve texturing the internal walls of the prostheses, controlling the membrane porosity and mechanical stiffness, and building guidance channels in the lumen of the protheses [35]. Interestingly these structural enhancements support a promising avenue for the adhesion and proliferation of SCs, which could accelerate the nerve regeneration process. However, apart from prosthesis design, the method of harvesting and refining SCs is also of prime importance. A repair might yield non-significant results if cultured SCs remained functionally inactive in a nerve prosthesis [16], which could results in local hypoxia in the early stages of axonal regeneration. This problem can be prevented by infusing SCs with oxygen-carrying hydrogels, such as fibrin-based hydrogels, to increase the sustained oxygen delivery to SCs [9]; however, despite the popularity of SCs, their harvesting remains invasive and difficult [7]. Moreover, the use of SCs has several ethical and clinical limitations, including the reduced proliferative capacity of SCs with no readily accessible source.
Advancement in the tissue engineering field has enabled researchers to transform stem cells sourced from adipose tissues, skin tissues, bone marrow, umbilical cord, etc., into cells having an SC-like phenotype and properties using less invasive procedures [36]. In particular, stem cells derived from non-neural tissue, such as mesenchymal stem cells (MSCs), have attracted great interest because of their remarkable differentiation potential [37,38]. Stem cells, for instance, skin-derived stem cells (SdSCs) in a collagen prosthesis, have shown the ability to improve peripheral nerve regeneration in terms of an increased number of myelinated axons [11]. Similarly, bone-marrow-derived stem cells (BMdSCs) are known to be helpful in successfully bridging nerve gaps by creating an adequate and favorable environment for the growth and myelination of regenerating axons, as well as the enhanced differentiation of BMdSCs into SCs [23]. In another study, the efficacy of the BMdSCs was assessed using a prosthesis filled with autologous BMdSCs, where axonal regeneration (myelinated axon number, the diameter of the regenerated fibers, and muscle weight), and functional recovery (amplitude and conduction velocity) were found to be comparable to autografting [17]. Similarly, bone marrow mononuclear cells (BMMnCs) seeded in a chitosan prosthesis, besides bridging the nerve gap, facilitated in the myelination of regenerating axons and also helped to attain functional recovery comparable to autologous nerve grafting [18].
Like BMdSCs, adipose-derived stem cells (ADSCs) can also differentiate into cells with SC-like properties (have the myelin-forming ability), and are reported to proliferate better when mixed with poloxamer hydrogel and aided in reinnervating muscle tissue [8]. In another instance, a neural tissue membrane containing differentiated ADSCs in a NeuraWrap™ prosthesis supported robust neural regeneration of a rat sciatic nerve in terms of axonal density, the diameter of nerve fibers, and myelination compared with NeuraWrap™ without ADSC membranes [6]. The cumulative benefits that ADSCs imparts include improved functional recovery and increased conservation of the muscle–mass ratio, nerve conduction velocity, and density of myelinated fibers [39].
Stem cells harvested from human umbilical cords and dental pulp can also promote neurite outgrowth [40,41], are more easily accessible than BMdSCs and ADSCs, and are reported to proliferative better than SCs [42]. Sciatic nerve repairs performed using these cells successfully stimulated regeneration and helped to improve functional recovery in dogs [19]. Differentiated human dental pulp stem cells (d-hDPSCs) in a NeuraWrap™ found to effectively increase neurite growth and the number of myelinated nerve fibers and blood vessels compared with the control group [7]. It has also been reported that amniotic fluid stem cells (AFSCs) possess the properties of mesenchymal and neural stem cells and can help to attain better functional recovery and a higher ratio of regenerated fibers than a control [43].
Mesenchymal stem cells (MSCs), mainly derived from bone marrow, are known to impart a therapeutic effect on tissue regeneration and modulate the immune system. They have attracted increasing research interest due to their possible use as support cells in nerve tissue engineering approaches [44]. In a comparative study, MSCs aligned within a collagen-based gel in a chitosan prosthesis demonstrated 90% regeneration compared to the repair performed using an SC-filled chitosan prosthesis [10]. A chitosan/poly(lactic-co-glycolic acid) (PLGA)-based prosthesis, when seeded with autologous MSCs, helped in bridging a segmental defect in a dog sciatic nerve, with the repair outcome being close to that of nerve autografting and better than that using the chitosan/PLGA-based scaffold alone [21]. Similarly, in another study, a chitosan/PLGA-based prosthesis filled with autologous bone marrow MSCs promoted regeneration of a median nerve in rhesus monkeys, where the recovery of nerve function in the treatment group was more efficient than that in the prosthesis-only group and comparable to autograft repair [20].
These findings suggest that adipose and skin tissues, as well as bone marrow, contain a pool of regenerative stem cells that can differentiate into cells with a Schwann-cell-like phenotype and properties, such as a myelin-forming ability; furthermore, they can be employed for repairing larger defects in peripheral nerves and may be of benefit for the treatment of peripheral nerve injuries. Table 1 reports studies on repairing critical-sized nerve defects ranging from 12 mm to 60 mm, highlights the delivery mode of cells, lists the methods adopted to access nerve regeneration, and presents research findings to show the effect of cell-based therapy on nerve regeneration. Each study in Table 1 was appraised and graded based on the following 11 selected key parameters;
  • Count of (i) regenerated axons, (ii) blood vessels, and (iii) FG-labeled motoneurons;
  • Measurement of (iv) axonal diameter, (v) myelin thickness, (vi) muscle weight ratio, (vii) compound muscle action potential, (viii) sciatic function index, (ix) nerve conduction velocity, (x) gap length, and (xi) follow-up time.
Each parameter was assigned a single point, except for gap length and follow-up time, which were given three points each, for a maximum possible total of fifteen points. A study was given one point if the repaired gap was 11 to 20 mm, two points for a gap of 21 to 40 mm, or three points for a gap greater than 40 mm. Similarly, a study was given one point if the follow-up time was up to four months, two points if the follow-up time was up to eight months, and three points if the follow-up time was greater than eight months. Studies with eight points or greater are marked with an asterisk sign in Table 1 and are of special interest because of their decisive role in crafting the conclusion of this manuscript.

4. Discussion and Perspective

Nerve prostheses made up of a variety of biomaterials and aided with either Schwann or stem cells derived from neural and non-neural tissues are becoming popular for repairing segmental defects in peripheral nerves. Table 1 highlights the use of a variety of cells in nerve prostheses for bridging critical-sized defects in peripheral nerves, along with the histological, electrophysiological, and functional assessment of nerve regeneration. The research findings confirmed that cell transplantation in a bioartificial prosthesis creates a favorable environment for achieving sustainable nerve regeneration and functional recovery across larger nerve defects, and has emerged as a novel therapeutic approach. Stem cells that are differentiated into cells having a Schwann-cell-like phenotype present a therapeutic modality and could be a potential replacement for nerve grafting. Axonal regeneration in the absence of a nerve prosthesis fails to completely bridge a nerve gap; however, a nerve may partially regenerate if a nerve prosthesis is used without any filler material (i.e., absence of stem cells or hydrogels). Conversely, cell transplantation in a prosthesis not only results in the complete bridging of a nerve gap but also helps to promote functional recovery.
The information presented in Table 1 was quantitively analyzed using GraphPad Prism 8.4.0 (GraphPad Software, San Diego, CA, USA) and is presented in Figure 2, which shows cell diversity and highlights the potential of various cells in bridging a wide range of nerve gaps. Figure 2a shows that SCs are a popular choice for cell therapy, where 33% of the studies employed them to promote nerve regeneration. Additionally, bone-marrow-derived mesenchymal cells also remained a center of interest, most likely because these cells—passing through pluripotency along neuronal cell lineages—proceed toward an SCs phenotype [4] that is chemically positive to SCs detection markers; they also account for 33% of the total of the studies. MSCs, besides mimicking SCs phenotypes, also contribute to neurogenesis by inducing the secretion of different neurotrophic factors, either directly from local precursors or indirectly from nearby activated astrocytes [45]. ADSCs were used by 10% of the studies examined, and stem cells procured from less popular sources each accounted for less than 5% of the studies examined. Figure 2b highlights the types of cells employed in different gap length repairs. SCs were used for repairing gaps with an average gap length up to 20 mm; interestingly, bone-marrow-derived MSCs have been employed for bridging almost double the nerve gap lengths compared to SCs.
An important aspect of this analysis is that it highlighted the use of stem cells differentiated into SCs in hydrogels for cell transplantation. The harvested cells can be directly implanted in their less differentiated state; however, the findings stress the in vitro treatment of these cells to transform them into SC-like cells before implantation. Although a mere 5% of studies (one study) reported that there is no significant difference in the repair outcome and both types of cells yield similar results, most of the studies, about 62% (13 studies), urged using differentiated stem cells for achieving significantly superior results. Similarly, cell suspension in a hydrogel improves the proliferation of the induced cells since the hydrogel becomes a source of long-time delivery of growth factors and neurotrophic nutrients that these cells secrete [46]. Here, it is also worth noting that cell suspensions with other biomaterials, such as collagen or gelatine, do not yield positive outcomes [5], and hence, induced cells must be mixed with appropriate hydrogels [16]. The death of transplanted cells in nerve prostheses could severely hamper the therapeutic effect of a repair [47] because the greater the quantity of these cells in the nerve prostheses, the higher the beneficial effect is [12]. However, this statement is contrary to the findings of study [5], (#3 in Table 1) and hence more studies on how the density of stem cells affects the quality of nerve regeneration are required.
Nerve repair using an empty prosthesis alone may assist axonal regeneration to some extent; however, this does not necessarily result in adequate functional outcomes [48]. Medium-sized nerve gaps can heal without cell therapy using hydrogels alone [5], but larger gaps always require cell-based treatment. Based on the studies reported here, cell-mediated nerve repair significantly helps to promote nerve regeneration over considerably longer distances. Cell therapy also provides the neurotrophins and extracellular matrix proteins required for nerve growth and myelination [49], and therefore, it represents a tool for future cell therapy applications in peripheral nerve regeneration by stimulating the proliferation of stem cells into SCs; however, the underlying mechanism remains elusive to date and the synergistic effects of stem cells need further exploration.
The repair outcome and recovery period depend on many factors, such as the repair quality, gap length, prosthesis material, and the quality (health) of the cells. An early sign of axonal regeneration and functional recovery, as measured by axonal counting and nerve conduction velocity, can be observed around the eighth week post repair; however, a period of twelve months is required to achieve functional recovery comparable to an autograft repair. This implies that a nerve prosthesis must be designed in such a way that the mechanical stiffness of its structural framework must support nerve regeneration up to twelve months without degrading or degenerating. A nerve prosthesis can be designed using any combination of synthetic biocompatible materials; however, the analysis advocates the use of collagen and chitosan as both materials significantly dwarf the competition. Thirty percent of the total number of studies reportedly used collagen for fabricating neural prostheses, and almost equal numbers reported using chitosan reinforced with PLGA and silk fibers.

5. Conclusions

The quality of the nerve repair performed using SCs can be approximated by using differentiated stem cells, which can boost nerve regeneration compared to the repair performed using a prosthesis alone. Mesenchymal stem cells, especially bone marrow-derived stem cells, are speculated to yield the most promising results and hence should be used in the treatment of larger defects in peripheral nerves. However, the results are less successful than autologous nerve grafting, the gold standard of nerve repair, which implies that cell therapy can assist nerve regeneration but it cannot replace nerve grafting altogether. It is noteworthy that a few studies have also reported that cell therapy is beneficial only for boosting nerve regeneration at the very beginning of the repair process and it does not necessarily make any difference afterward [50]. Hence, the possibility of stem cells inducing a transient positive effect on nerve regeneration should not be overlooked. However, Brown et al. argued that this occurs only for a gap of less than 30 mm, and the gap length should be greater than 30 mm to observe any significant difference compared to a control [16].
An evident drawback of the studies reported herein is that 52% of the studies employed a rat nerve injury model to observe cells in promoting nerve regeneration, even though a rat model is generally a poor model for the repair of human critical gap defects due to its small size and species-specific neurobiological regenerative profile [51]. In contrast, the trend of using larger mammals remained consistently low, possibly due to operational difficulties, post-operative housing/care, and financial and ethical restrictions. To this end, 38% of the studies reported the use of: dogs (five studies), monkeys (two studies), or goats (one study). Furthermore, it should also be acknowledged that the outcomes of the reported studies were never translated into clinical trials, which unfortunately puts a stern question mark on the current efficacy of this repair approach.
Nonetheless, cell-based therapy possesses tremendous potential for improving nerve regeneration; however, the limited availability of neural-based stem cells makes it highly challenging. Stem cells procured from other sources, such as bone marrow and adipose tissues, require a complex process of cell harvesting and adaption, which limits the reliability of this technique. Cell death soon after transplantation or their limited life span may also limit their efficacy; however, as this work is still in its infancy, the future of cell-based therapy on neural regeneration is promising.

Author Contributions

Manuscript concept and design of the study: M.S.U.S.; literature search and initial manuscript drafting: M.S.U.S. and M.B.; critical revision: M.B. and G.T.; final approval for publication: M.S.U.S. and G.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Archibald, S.J.; Shefner, J.; Krarup, C.; Madison, R.D. Monkey median nerve repaired by nerve graft or collagen nerve guide tube. J. Soc. Neurosci. 1995, 15, 4109–4123. [Google Scholar] [CrossRef]
  2. Daly, W.; Yao, L.; Zeugolis, D. A biomaterials approach to peripheral nerve regeneration: Bridging the peripheral nerve gap and enhancing functional recovery. J. R. Soc. Interface 2012, 9, 202–221. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. O’Rourke, C.; Day, A.G.E.; Murray-Dunning, C.; Thanabalasundaram, L.; Cowan, J.; Stevanato, L.; Phillips, J.B. An allogeneic “off the shelf” therapeutic strategy for peripheral nerve tissue engineering using clinical grade human neural stem cells. Sci. Rep. 2018, 8, 2951. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Ladak, A.; Olson, J.; Tredgeta, E.E.; Gordon, T. Differentiation of mesenchymal stem cells to support peripheral nerve regeneration in a rat model. Exp. Neurol. 2011, 228, 242–252. [Google Scholar] [CrossRef]
  5. Evans, G.R.D.; Brandt, K.; Katz, S. Bioactive poly(l-lactic acid) conduits seeded with Schwann cells for peripheral nerve regeneration. Biomaterials 2002, 23, 841–848. [Google Scholar] [CrossRef]
  6. Georgiou, M.; Golding, J.P.; Loughlin, A.J.; Kingham, P.J.; Phillips, J.B. Engineered neural tissue with aligned, differentiated adipose-derived stem cells promotes peripheral nerve regeneration across a critical sized defect in rat sciatic nerve. Biomaterials 2015, 37, 242–251. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Sanen, K.; Martens, W.; Georgiou, M.; Ameloot, M.; Lambrichts, I.; Phillips, J. Engineered neural tissue with Schwann cell differentiated human dental pulp stem cells: Potential for peripheral nerve repair? J. Tissue Eng. Regen. Med. 2017, 11, 3362–3372. [Google Scholar] [CrossRef] [Green Version]
  8. Allbright, K.O.; Bliley, J.M.; Havis, E.; Kim, D.-Y.; Dibernardo, G.A.; Grybowski, D.; Waldner, M.; James, I.B.; Sivak, W.N.; Rubin, J.P.; et al. Delivery of adipose-derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration. Muscle Nerve 2018, 58, 251–260. [Google Scholar] [CrossRef]
  9. Ma, T.; Zhu, L.; Yang, Y.; Quan, X.; Huang, L.; Liu, Z.; Luo, Z. Enhanced in vivo survival of Schwann cells by a synthetic oxygen carrier promotes sciatic nerve regeneration and functional recovery. J. Tissue Eng. Regen. Med. 2018, 12, e177–e189. [Google Scholar] [CrossRef]
  10. Gonzalez-Perez, F.; Hernández, J.; Heimann, C.; Phillips, J.B.; Udina, E.; Navarro, X. Schwann cells and mesenchymal stem cells in laminin-or fbronectin-aligned matrices and regeneration across a critical size defect of 15 mm in the rat sciatic nerve. J. Neurosurg. Spine 2018, 28, 109–118. [Google Scholar] [CrossRef]
  11. Marchesi, C.; Pluderi, M.; Colleoni, F.; Belicchi, M.; Meregalli, M.; Farini, A.; Porretti, L. Skin-derived stem cells transplanted into resorbable guides provide functional nerve regeneration after sciatic nerve resection. Glia 2007, 55, 425–438. [Google Scholar] [CrossRef] [PubMed]
  12. Ansselin, A.D.; Fink, T.; Davey, D.F. Peripheral nerve regeneration through nerve guides seeded with adult Schwann cells. Neuropathol. Appl. Neurobiol. 1997, 23, 387–398. [Google Scholar] [CrossRef] [PubMed]
  13. Sinis, N.; Schaller, H.E.; Schulte-Eversum, C.; Schlosshauer, B.; Doser, M.; Dietz, K.; Haerle, M. Nerve regeneration across a 2-cm gap in the rat median nerve using a resorbable nerve conduit filled with Schwann cells. J. Neurosurg. 2005, 103, 1067–1076. [Google Scholar] [CrossRef] [PubMed]
  14. Wakao, S.; Hayashi, T.; Kitada, M.; Kohama, M.; Matsue, D.; Teramoto, N.; Iida, H. Long-term observation of auto-cell transplantation in non-human primate reveals safety and efficiency of bone marrow stromal cell-derived Schwann cells in peripheral nerve regeneration. Exp. Neurol. 2010, 223, 537–547. [Google Scholar] [CrossRef]
  15. Cheng, B.; Chen, Z. Fabricating autologous tissue to engineer artificial nerve. Microsurgery 2002, 22, 133–137. [Google Scholar] [CrossRef]
  16. Brown, R.E.; Erdmann, D.; Lyons, S.F.; Suchy, H. The Use of Cultured Schwann Cells in Nerve Repair in a Rabbit Hind-Limb Model. J. Reconstr. Microsurg. 1996, 12, 149–152. [Google Scholar] [CrossRef]
  17. Kaizawa, Y.; Kakinoki, R.; Ikeguchi, R.; Ohta, S.; Noguchi, T.; Oda, H.; Matsuda, S. Bridging a 30 mm defect in the canine ulnar nerve using vessel-containing conduits with implantation of bone marrow stromal cells. Microsurgery 2016, 36, 316–324. [Google Scholar] [CrossRef]
  18. Muheremu, A.; Chen, L.; Wang, X.; Wei, Y.; Gong, K.; Ao, Q. Chitosan nerve conduits seeded with autologous bone marrow mononuclear cells for 30 mm goat peroneal nerve defect. Sci. Rep. 2017, 7, 44002. [Google Scholar] [CrossRef] [Green Version]
  19. Cui, Y.; Yao, Y.; Zhao, Y.; Xiao, Z.; Cao, Z.; Han, S.; Li, X.; Huan, Y.; Pan, J.; Dai, J. Functional collagen conduits combined with human mesenchymal stem cells promote regeneration after sciatic nerve transection in dogs. J. Tissue Eng. Regen. Med. 2018, 12, 1285–1296. [Google Scholar] [CrossRef] [Green Version]
  20. Hu, N.; Wu, H.; Xue, C.; Gong, Y.; Wu, J.; Xiao, Z. Long-term outcome of the repair of 50 mm long median nerve defects in rhesus monkeys with marrow mesenchymal stem cells-containing, chitosan-based tissue engineered nerve grafts. Biomaterials 2013, 34, 100–111. [Google Scholar] [CrossRef]
  21. Ding, F.; Wu, J.; Yang, Y. Use of tissue-engineered nerve grafts consisting of a chitosan/poly(lactic- co-glycolic acid)-based scaffold included with bone marrow mesenchymal cells for bridging 50-mm dog sciatic nerve gaps. Tissue Eng. Part. A. 2010, 16, 3779–3790. [Google Scholar] [CrossRef] [PubMed]
  22. Xue, C.; Hu, N.; Gu, Y.; Yang, Y.; Liu, Y.; Liu, J.; Gu, X. Joint use of a chitosan/PLGA scaffold and MSCs to bridge an extra large gap in dog sciatic nerve. Neurorehabilit. Neural Repair 2012, 26, 96–106. [Google Scholar] [CrossRef] [PubMed]
  23. Xue, C.; Ren, H.; Zhu, H.; Gu, X.; Guo, Q.; Zhou, Y.; Yang, Y. Bone marrow mesenchymal stem cell-derived acellular matrix-coated chitosan/silk scaffolds for neural tissue regeneration. J. Mater. Chem. B 2017, 5, 1246–1257. [Google Scholar] [CrossRef]
  24. Sahar, M.S.U.; Barton, M.; Tansley, G.D. Bridging larger gaps in peripheral nerves using neural prosthetics and physical therapeutic agents. Neural Regen. Res. 2019, 14, 1109. [Google Scholar] [CrossRef]
  25. Babu, P.; Behl, A.; Chakravarty, B.; Bhandari, P.S. Entubulation techniques in peripheral nerve repair. Indian J. Neurotrauma 2008, 5, 15–20. [Google Scholar] [CrossRef]
  26. Mantovani, C.; Terenghi, G.; Shawcross, S.G. Isolation of Adult Stem Cells and Their Differentiation to Schwann Cells; Humana Press: Totowa, NJ, USA, 2012; pp. 47–57. [Google Scholar] [CrossRef]
  27. Widgerow, A.D.; Salibian, A.A.; Lalezari, S.; Evans, G.R. Neuromodulatory nerve regeneration: Adipose tissue-derived stem cells and neurotrophic mediation in peripheral nerve regeneration. J. Neurosci. Res. 2013, 91, 1517–1524. [Google Scholar] [CrossRef]
  28. Kolar, M.K.; Kingham, P.J. Regenerative effects of adipose-tissue-derived stem cells for treatment of peripheral nerve injuries. Biochem. Soc. Trans. 2014, 42, 697–701. [Google Scholar] [CrossRef]
  29. Pereira Lopes, F.R.; Frattini, F.; Marques, S.A.; de Almeida, F.M.; de Moura Campos, L.C.; Langone, F.; Martinez, A.M.B. Transplantation of bone-marrow-derived cells into a nerve guide resulted in transdifferentiation into Schwann cells and effective regeneration of transected mouse sciatic nerve. Micron 2010, 41, 783–790. [Google Scholar] [CrossRef]
  30. Ide, C. Peripheral nerve regeneration. Neurosci. Res. 1996, 25, 101–121. [Google Scholar] [CrossRef]
  31. Levi, A.; Guenard, V.; Aebischer, P.; Bunge, R.P. The functional characteristics of Schwann cells cultured from human peripheral nerve after transplantation into a gap within the rat sciatic nerve. J. Neurosci. 1994, 14, 1309–1319. [Google Scholar] [CrossRef] [Green Version]
  32. Gulati, A.K. Evaluation of acellular and cellular nerve grafts in repair of rat peripheral nerve. J. Neurosurg. 1988, 68, 117–123. [Google Scholar] [CrossRef]
  33. Wrobel, S.; Morano, M.; Meyer, C.; Shahar, A.; Ziv, O.; Haastert-Talini, K.; Grothe, C. Development of cell-enhanced chitosan scaffolds to overcome long gaps after peripheral nerve injury. Cytotherapy 2014, 16, S102. [Google Scholar] [CrossRef]
  34. Kim, S.-M.; Lee, S.-K.; Lee, J.-H. Peripheral nerve regeneration using a three dimensionally cultured schwann cell conduit. J. Craniofacial Surg. 2007, 18, 475–488. [Google Scholar] [CrossRef] [PubMed]
  35. Bell, J.H.A.; Haycock, J.W. Read: Next Generation Nerve Guides: Materials, Fabrication, Growth Factors, and Cell Delivery. Tissue Eng. Part. B Rev. 2012, 18, 116–128. [Google Scholar] [CrossRef] [PubMed]
  36. Resch, A.; Wolf, S.; Mann, A.; Weiss, T.; Stetco, A.L.; Radtke, C. Co-culturing human adipose derived stem cells and schwann cells on spider silk—A new approach as prerequisite for enhanced nerve regeneration. Int. J. Mol. Sci. 2019, 20, 71. [Google Scholar] [CrossRef] [Green Version]
  37. Pittenger, M.F.; Mackay, A.M.; Beck, S.C.; Jaiswal, R.K.; Douglas, R.; Mosca, J.D.; Marshak, D.R. Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284, 143–147. [Google Scholar] [CrossRef] [Green Version]
  38. Prockop, D.J. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997, 71–74. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Liu, G.-B.; Cheng, Y.X.; Feng, Y.K.; Pang, C.J.; Li, Q.; Wang, Y. Adipose-derived stem cells promote peripheral nerve repair. Arch. Med. Sci. 2011, 7, 592–596. [Google Scholar] [CrossRef]
  40. Peng, J.; Feng, X.Y.; Cui, B.L.; Law, F.; Jiang, X.W.; Yang, L.Y.; Huang, T.H. Human umbilical cord Wharton’s jelly-derived mesenchymal stem cells differentiate into a Schwann-cell phenotype and promote neurite outgrowth in vitro. Brain Res. Bull. 2011, 84, 235–243. [Google Scholar] [CrossRef]
  41. Guo, Z.-Y.; Sun, X.; Xu, X.L.; Zhao, Q.; Peng, J.; Wang, Y. Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms. Neural Regen. Res. 2015, 10, 651. [Google Scholar] [CrossRef]
  42. Xiao, B.; Rao, F.; Guo, Z.Y.; Sun, X.; Wang, Y.G.; Liu, S.Y.; Peng, J. Extracellular matrix from human umbilical cord-derived mesenchymal stem cells as a scaffold for peripheral nerve regeneration. Neural Regen. Res. 2016, 11, 1172. [Google Scholar] [CrossRef] [PubMed]
  43. Su, C.F.; Chang, L.H.; Kao, C.Y.; Lee, D.C.; Cho, K.H.; Kuo, L.W.; Chiu, M. Application of amniotic fluid stem cells in repairing sciatic nerve injury in minipigs. Brain Res. 2018, 1678, 397–406. [Google Scholar] [CrossRef] [PubMed]
  44. Liu, Y.; Wang, L.; Kikuiri, T.; Akiyama, K.; Chen, C.; Xu, X.; Shi, S. Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α. Nat. Med. 2011, 17, 1594–1601. [Google Scholar] [CrossRef] [PubMed]
  45. Uccelli, A.; Laroni, A.; Freedman, M.S. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol. 2011, 649–656. [Google Scholar] [CrossRef]
  46. António, J.B.O.G.S.; RuI, L.G.R.; Nuno, J.C.S.; Jeffrey, M.G. Adipose Tissue Derived Stem Cells Secretome: Soluble Factors and Their Roles in Regenerative Medicine. Curr. Stem. Cell Res. Ther. 2010, 5, 103–110. [Google Scholar] [CrossRef] [Green Version]
  47. Zhang, W.; Zhang, L.; Liu, J.; Zhang, L.; Zhang, J.; Tang, P. Repairing sciatic nerve injury with an EPO-loaded nerve conduit and sandwiched-in strategy of transplanting mesenchymal stem cells. Biomaterials 2017, 142, 90–100. [Google Scholar] [CrossRef]
  48. You, H.; Wei, L.; Liu, Y.; Oudega, M.; Jiao, S.S.; Feng, S.N.; Li, B.C. Olfactory ensheathing cells enhance Schwann cell-mediated anatomical and functional repair after sciatic nerve injury in adult rats. Exp. Neurol. 2011, 229, 158–167. [Google Scholar] [CrossRef]
  49. Lopatina, T.; Kalinina, N.; Karagyaur, M.; Stambolsky, D.; Rubina, K.; Revischin, A.; Tkachuk, V. Adipose-Derived Stem Cells Stimulate Regeneration of Peripheral Nerves: BDNF Secreted by These Cells Promotes Nerve Healing and Axon Growth De Novo. PLoS ONE 2011, 6, e17899. [Google Scholar] [CrossRef]
  50. Boecker, A.H.; Bozkurt, A.; Kim, B.S.; Altinova, H.; Tank, J.; Deumens, R.; Tolba, R.; Weis, J.; Brook, G.A.; Pallua, N.; et al. Cell-enrichment with olfactory ensheathing cells has limited local extra beneficial effects on nerve regeneration supported by the nerve guide Perimaix. J. Tissue Eng. Regen. Med. 2018, 12, 2125–2137. [Google Scholar] [CrossRef]
  51. Kaplan, H.M.; Mishra, P.; Kohn, J. The overwhelming use of rat models in nerve regeneration research may compromise designs of nerve guidance conduits for humans. J. Mater. Sci. Mater. Med. 2015, 26. [Google Scholar] [CrossRef] [Green Version]
Prosthesis 02 00014 g001 550
Figure 1. Literature search methodology according to PRISMA guidelines.
Figure 1. Literature search methodology according to PRISMA guidelines.
Prosthesis 02 00014 g001
Prosthesis 02 00014 g002 550
Figure 2. The use of cell therapies aimed at bridging critical-sized segmental nerve defects: (a) the number of studies reported on type and (b) the average gap length repaired by each type of cell therapy. SCs: Schwann cells, SDSCs: Skin-derived stem cells, ADSCs: Adipose-derived stem cells, MSCs: Bone-marrow-derived mesenchymal cells, hDPSCs: Human dental pulp stem cells, hNSCs: Human neural stem cells, BMMnCs: Bone marrow mononuclear cells, BMStCs: Bone marrow stromal cells.
Figure 2. The use of cell therapies aimed at bridging critical-sized segmental nerve defects: (a) the number of studies reported on type and (b) the average gap length repaired by each type of cell therapy. SCs: Schwann cells, SDSCs: Skin-derived stem cells, ADSCs: Adipose-derived stem cells, MSCs: Bone-marrow-derived mesenchymal cells, hDPSCs: Human dental pulp stem cells, hNSCs: Human neural stem cells, BMMnCs: Bone marrow mononuclear cells, BMStCs: Bone marrow stromal cells.
Prosthesis 02 00014 g002
Table
Table 1. Repairing critical-sized defects in peripheral nerves using a nerve prosthesis aided by cell-based therapy. PGA: Polyglycolic acid, PLA: Polylactic acid, PLGA: Poly(lactic-co-glycolic acid), PLLA: Poly(L-lactic acid), PLCL: Poly(L-lactide-ε-caprolactone), PTFE: Polytetrafluoroethylene, PFTBA: Perfluorotributylamine, TMC/CL: Trimethylenecarbonate-co-epsilon-caprolactone, d: differentiated, ud: undifferentiated, SCs: Schwann cells, MSCs: Mesenchymal stem cells, ADSCs: Adipose-derived stem cells, BMStCs: Bone marrow stromal cell, BMMnCs: Bone marrow mononuclear cells, GFP: Green fluorescent protein, SFI: Sciatic function index, NCV: Nerve conduction velocities, CMAP: Compound muscle action potential, CUiS: Contralateral uninjured side, CUiN: Contralateral uninjured nerve, FG: Fluorogold. Studies marked with an asterisk are of special interest (see Section 3 for further detail).
Table 1. Repairing critical-sized defects in peripheral nerves using a nerve prosthesis aided by cell-based therapy. PGA: Polyglycolic acid, PLA: Polylactic acid, PLGA: Poly(lactic-co-glycolic acid), PLLA: Poly(L-lactic acid), PLCL: Poly(L-lactide-ε-caprolactone), PTFE: Polytetrafluoroethylene, PFTBA: Perfluorotributylamine, TMC/CL: Trimethylenecarbonate-co-epsilon-caprolactone, d: differentiated, ud: undifferentiated, SCs: Schwann cells, MSCs: Mesenchymal stem cells, ADSCs: Adipose-derived stem cells, BMStCs: Bone marrow stromal cell, BMMnCs: Bone marrow mononuclear cells, GFP: Green fluorescent protein, SFI: Sciatic function index, NCV: Nerve conduction velocities, CMAP: Compound muscle action potential, CUiS: Contralateral uninjured side, CUiN: Contralateral uninjured nerve, FG: Fluorogold. Studies marked with an asterisk are of special interest (see Section 3 for further detail).
Study
No.		Cell TypeMode of Cell DeliveryGap (mm)Animal ModelAssessment of Nerve RegenerationResearch Findings
SubjectGroupsHistological
Assessments		Functional
Assessments
1 *Human neural stem cellsCollagen prosthesis with an inner lining of engineered neural tissues (d-neural stem cells + collagen).12Rat sciatic nerveG1: Autograft
G2: Treatment
G3: Prosthesis alone		Two months
No. of Axons
G1: 5000, G2: 4300, G3: 5200
Axonal diameter
G1: 0.9, G2: 1.2, G3: 0
Myelin thickness
G1: 0.63, G2: 0.57, G3: 0
No. of blood vessels
G1: 18, G2: 23, G3: 0
Gastrocnemius weight (% of control)
G1: 42, G2: 25, G3: 17		Two months
CMAP (gastrocnemius muscle)
G1: 2.5, G2: 7.5, G3: 3.7		Enhanced growth of neurites and vasculature along with reinnervation of the target muscle [3].
2MSCsInjection of d-MSCs into the lumen of the collagen prosthesis12Rat sciatic nerveG1: Reverse autograft
G2: Prosthesis with ud-MSCs
G3: Prosthesis with d-MSCs
G4: Prosthesis with SCs
G5: Prosthesis alone		Three months
No. of FG-labeled motoneurons
G1: 1310, G2: 430, G3: 605, G4: 800, G5: 300		Three months
CMAP
G1: 2.2, G2: 1.3, G3: 1.2, G4: 1.2, G5: 1.15, Control (healthy): 2.5		Sufficiently supported limited axonal regeneration that was comparable to implant repair using SCs [4].
3SCsInjection of SCs in collagen gel into the lumen of the PLLA prosthesis12Rat sciatic nerveG1: Reverse autograft
G2: Prosthesis with 1 × 104 SC/mL
G3: Prosthesis with 1 × 106 SC/mL
G4: Prosthesis with gel only
G5: Silicone prosthesis		Four months
No. of Axons
G1: 23,000, G2: 25,000, G3: 17,000, G4: 27,000, G5: 30,000
Gastrocnemius muscle weight
G1: 1.5, G2: 1.25, G3: 1.1, G4: 1.2, G5: 1.1		Four months
Sciatic function index score
G1: 86.90
G2: 84.74
G3: 89.92
G4: 83.74
G5: 74.43		Regeneration in all groups with no significant difference between groups [5].
4d-ADSCsSheet developed from ADSCs in collagen gel was placed inside Neura-Wrap™15Rat sciatic nerveG1: Autograft
G2: Treatment
G3: NeuraWrap alone		Two months
Myelin thickness
G1 and G3: Lower in G3 compared to the G1;
G1 and G2: No difference		Not testedAxonal regeneration in the distal stump was 3.5 times greater in G2 than G3 [6].
5d- human dental pulp stem cellsSheets of stem cells in the Neura-Wrap™ prosthesis15Rat sciatic nerveG1: Allograft
G2: Treatment
G3: Prosthesis alone
Two months
No. of Axons
G1: ≈10,000, G2: ≈1000, G3: ≈800
No. of blood vessels
G1: 260, G2: 250, G3: 100		Not testedPositive effect on the regeneration of nerve tissue in vivo [7].
6ADSCsADSCs mixed in poloxamer and injected into the lumen of the PCL prosthesis15Rat sciatic nerveG1: Reverse autograft
G2: Treatment
G3: Prosthesis with hydrogel
G4: Prosthesis with ADSCs
G5: Prosthesis only		One and a half months
Axonal growth
G2: 8.23, G3: 7.1, G4: 6, G5: 5.9
Gastrocnemius weight ratio
G1–G6: 0.29 ± 0.06		Not testedADSCs in poloxamer hydrogel could proliferate better and demonstrated the longest axonal regrowth [8].
7SCsPFTBA hydrogel mixed with SCs and injected into the lumen of a collagen-chitosan prosthesis15Rat sciatic nerveG1: Autograft
G2: Treatment
G3: SCs only
G4: Hydrogel only
G5: Prosthesis alone		Three months
No. of Axons
G1: 1.4, G2: 1.3, G3: 1.0, G4: 1.1, G5: 0.6 (×104)
Axonal diameter
G1: 3.8, G2: 3.85, G3: 2.5, G4: 2.55, G5: 1.7
FG-labeled motoneurons
G1: 530, G2: 505, G3: 415, G4: 410, G5: 340		Three months
SFI score
G1: −37, G2: −40, G3: −51, G4: −53, G5: −68
NCV
G1: 23, G2: 22, G3: 18, G4: 19, G5: 15		Prosthesis containing SCs in PFTBA hydrogel helped with SCs proliferation and the formation of vascular networks [9].
8SCsMSCs or SCs in collagen-fibronectin-based gels and placed inside the chitosan prosthesis15Rat sciatic nerveG1: Autograft
G2: Collagen- fibronectin and MSCs
G3: Collagen- fibronectin and SCs
G4: Fibronectin prosthesis alone		Four months
No. of Axons
G1: 14,409, G2: 6192, G3: 7656, G4: 3105		Four months
CMAP of gastrocnemius
G1: 60, G2: 34, G3: 54, G4: 35		SC-seeded chitosan prosthesis is a potential alternative to the autograft for repairing long-gap peripheral nerve injuries [10].
9SDSCsSDSCs labeled with GFP placed inside PLA-TMC
or collagen prosthesis		16Rat sciatic nerveG1: PLA-TMC prosthesis + SdSCs
G2: PLA-TMC prosthesis + PBS
G3: Collagen prosthesis + SdSCs
G4: Collagen prosthesis + PBS		Three months
No. of Axons
G1: 780, G3: 1125
Axonal diameter
G1: 2.8, G3: 3.3, Contralateral nerve: 6.7
Density of myelinated axons
G1: 3661, G2: 2361, G3: 3835, G4: 2779		Three months
SFI score
G1: −75, G2: −82, G3: −69.4, G4: −76
NCV
G1: 14.71, G3: 16.51, Control: 22.6		Collagen prosthesis yielded significantly better results than the PLA-TMC prosthesis [11].
10SCsInjection of SCs into the lumen of a collage prosthesis18Rat sciatic nerveG1: Prosthesis with >0.5 × 106 SCs
G2: Prosthesis <0.5 × 106 SCs
G3: Prosthesis with PBS		Six months
No. of myelinated axons
G1: 13,000, G2: 4800, G3: 0, Normal nerve: 6000		Twelve months
SFI
G1: −70, G2: −80, G3: 0
NCV operated side
G1: 29, G2: 28, G3: 0		Increasing the number of cells in the guides had a greater beneficial effect [12].
11SCsInjection of SCs in matrigel into the lumen of a TMC/CL prosthesis20Rat median nerveG1: Reverse autograft
G2: Treatment
G3: Prosthesis alone		Nine months
No. of Axons
G1: 3453, G2: 4402, G3: 0, Normal: 2361
Myelin thickness
G1: 1.086, G2: 0.954, G3: 0, Normal: 1.631		Nine months
CMAP
G1, G2: No difference
G3: 0		Functional recovery comparable to autograft repair [13].
12MSCsInduction of d-MSCs into PTFE prosthesis20Monkey median nerveG1: Treatment
G2: Prosthesis alone		Twelve months
NF-positive area/total nerve area
G1: 51.5, G2: 33.3		Twelve months
CMAP
G1: 7.5, G2: 2.1
NCV
G1: 13.5, G2: 10.2, Control: 18		Transplantation of stem cells was helpful for nerve regeneration [14].
13SCsInjection of SCs into the lumen of a polyglactin prosthesis20Rabbit sciatic nerveG1: Treatment
G2: Autograft		Two months
No. of Axons
G1: 900, G2: 1102		Not testedAxonal regeneration was observed, even in the distal nerve stump [15].
14SCsSCs mixed in gelatin and pipetted into the lumen of the PGA prosthesis30Rabbit peroneal nerveG1: Treatment
G2: Prosthesis with gelatine only		Four months
Scoring of myelinations (3—good, 2—fair, 1—poor, P—proximal, M—middle, D—distal)
G1: 2.7 P, 1.5 M, 1.0 D
G2: 3.0 P, 1.7 M, 1.4 D		Four months
NCV (% of the NCV of the CUiS)
G1: 94.7, G2: 96.5		Local initial effect on nerve regeneration;
a gap of 30 mm was not enough to observe a significant difference [16].
15 *ud-BMStCsInjection of autologous ud-BMSCs into the lumen of a PLCL prosthesis30Dog ulnar nerveG1: Reverse autograft
G2: Prosthesis with ud-BMSCs		Six months
No. of Axons
G1: 7032, G2: 7165
Axonal diameter
G1: 1.73, G2: 2.09
Six months
CMAP
G1: 25.3, G2: 10.9
NCV
G1: 23.5, G2: 31.6 		A viable option for the treatment of peripheral nerve injuries [17].
16 *BMMnCsInjection of autologous BmMnCs into the lumen of a chitosan prosthesis 30Goat peroneal nerveG1: Autograft
G2: Prosthesis with BmMnCs
G3: Prosthesis with Basal Medium Eagle
Twelve months
Axonal diameter
G1: 3.60, G2: 3.67, G3: 0, Normal: 6.12
Myelin thickness
G1: 0.97, G2: 0.88, G3: 0, Normal: 1.32		Twelve months
NCV
G1: 51, G2: 37, G3: 0		BmMnCs not only helped in bridging longer defects but also induced functional recovery [18].
17 *MSCsInjection of MSCs into the lumen of a collagen prosthesis35Dog sciatic nerveG1: Autograft
G2: Treatment
G3: Prosthesis alone		Nine months
Axonal diameter
G1: 7.7, G2: 3.6, G3: 2.5
Thickness of neo-fibers
G1: 0.75, G2: 0.33, G3: 0.08
Gastrocnemius weight (%)
G1: 48, G2: 69, G3: 84, G4: 90		Nine months
CMAP ratio
G1: 77, G2: 68, G3: 46		Axonal regeneration and improved functional recovery [19].
18 *MSCsInjection of an autologous bone marrow MSC suspension in a chitosan/PLGA prosthesis50Monkey median nerveG1: Autograft
G2: Treatment
G3: Prosthesis alone		Twelve months
Axons diameter
G1: 5.7, G2: 4.7, G3: 4, Normal: 7.1
Myelin thickness
G1: 1.1, G2: 0.8, G3: 0.6, Normal: 1.7
FG-labeled motoneurons
G1: 15,800, G2: 15,700, G3: 15,050, Normal: 17,500		Twelve months
CMAP
G1: 6.8, G2: 3.9, G3: 3.8, Normal: 12.1
NCV
G1: 30, G2: 19, G3: 13, Normal: 87		Repair similar to autograft repair and better than the repair done using a prosthesis alone [20].
19 *MSCsInjection of an autologous bone marrow MSC suspension in a chitosan/PLGA prosthesis50Dog sciatic nerveG1: Reverse autograft
G2: Prosthesis alone
G3: Treatment		Six months
Myelin thickness
G1: 1.3, G2: 1.1, G3: 1.4, Normal: 2.4
Density of myelinated fibers
G1: 6, G2: 4.1, G3: 5.8, Normal: 11.2
Gastrocnemius muscle weight ratio
G1: 0.92, G2: 0.79, G3: 0.86, G4: 0.6		Six months
CMAPG1: 9, G2: 6, G3: 9.6, Normal: 15.8
NCVG1: 41, G2: 23, G3: 39, Normal: 101		Nerve regeneration and functional recovery comparable to autograft repair [21].
20 *MSCsInjection of an autologous MSC suspension in a chitosan/PLGA prosthesis60Dog sciatic nerveG1: Autograft
G2: Prosthesis with MSCs
G3: Prosthesis alone		Twelve months
Axonal diameter
G1: 5.2, G2: 4.1, G3: 4.0, CUiS: 8.1
Myelin thickness
G1: 1.3, G2: 1.1, G3: 0.8, CUiS: 1.7
Muscle weight ratio Gastronomes G1: 0.82, G2: 0.78, G3: 0.76, G4: 0.25
FG-labeled motoneurons
G1: 18,300, G2: 17,500, G3: 15,000, CUiS: 21,000		Twelve months
CMAP
G1: 10, G2: 6.2, G3: 5.5, CUiN: 14
NCV
G1: 36, G2: 25, G3: 21, CUiN: 90		Repair outcomes were similar to the autograft repair and better than those of prosthesis alone [22].
21 *MSCsInjection of bone-marrow-derived mesenchymal stem cells into the lumen of a chitosan/silk prosthesis60Dog sciatic nerveG1: Reverse autograft
G2: Prosthesis with BMSCs		Twelve months
Axonal diameter
G1: 6.2, G2: 6.1, CUiS: 10.1
Myelin thickness
G1: 1.3, G2: 1.2, CUiS: 2.2
FG-labeled motoneurons
G1: 14,000, G2: 13,000, CUiS: 21,000
Muscle weight ratio (%)
Gastronomes G1: 67, G2: 43, G3: 25		Twelve months
CMAP
G1: 11, G2: 9, CUiS: 23
NCV
G1: 34, G2: 33, CUiS: 86		Repair outcomes of the treatment group were comparable to autograft repair [23].
Note: All results are reported relative to the findings in proximal stumps. Axonal diameter, axonal growth (neurite length), and myelin thickness are reported in micrometers (µm); NCV is reported in meters per second (m/s); and CMAP is reported in millivolts (mV).

Share and Cite

MDPI and ACS Style

Sahar, M.S.U.; Barton, M.; Tansley, G. A Systematic Review of the Effectiveness of Cell-Based Therapy in Repairing Peripheral Nerve Gap Defects. Prosthesis 2020, 2, 153-167. https://doi.org/10.3390/prosthesis2030014

AMA Style

Sahar MSU, Barton M, Tansley G. A Systematic Review of the Effectiveness of Cell-Based Therapy in Repairing Peripheral Nerve Gap Defects. Prosthesis. 2020; 2(3):153-167. https://doi.org/10.3390/prosthesis2030014

Chicago/Turabian Style

Sahar, Muhammad Sana Ullah, Matthew Barton, and Geoffrey Tansley. 2020. "A Systematic Review of the Effectiveness of Cell-Based Therapy in Repairing Peripheral Nerve Gap Defects" Prosthesis 2, no. 3: 153-167. https://doi.org/10.3390/prosthesis2030014

APA Style

Sahar, M. S. U., Barton, M., & Tansley, G. (2020). A Systematic Review of the Effectiveness of Cell-Based Therapy in Repairing Peripheral Nerve Gap Defects. Prosthesis, 2(3), 153-167. https://doi.org/10.3390/prosthesis2030014

Article Metrics

Back to TopTop