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Development of biosynthetic conduits for peripheral nerve repair
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Peripheral nerve injuries are often associated with significant loss of nervous tissue leading to poor restoration of function following repair of injured nerves. Although the injury gap could be bridged by autologous nerve graft, the limited access to donor material and additional morbidity such as loss of sensation and scarring have prompted a search for biosynthetic nerve transplants.

The present thesis investigates the effects of a synthetic matrix BD™ PuraMatrix™ peptide (BD)hydrogel, alginate/fibronectin gel and fibrin glue combined with cultured rat Schwann cells or human bone marrow derived mesenchymal stem cells (MSC) on neuronal regeneration and muscle recovery after peripheral nerve injury in adult rats.

In a sciatic nerve injury model, after 3 weeks postoperatively, the regenerating axons grew significantly longer distances within the conduits filled with BD hydrogel if compared with the alginate/fibronectin gel. The addition of rat Schwann cells to the BD hydrogel drastically increased regeneration distance with axons crossing the injury gap and entering into the distal nerve stump. However, at 16 weeks the number of regenerating spinal motoneurons was decreased to 49% and 31% in the BD hydrogel and alginate/fibronectin groups respectively. The recovery of the gastrocnemius muscle was also inferior in both experimental groups if compared with the nerve graft. The addition of the cultured Schwann cells did not further improve the regeneration of motoneurons and muscle recovery.

The growth-promoting effects of the tubular conduits prepared from fibrin glue were also studied following repair of short and long peripheral nerve gaps. Retrograde neuronal labeling demonstrated that fibrin glue conduit promoted regeneration of 60% of injured sensory neurons and 52% of motoneurons when compared with the autologous nerve graft. The total number of myelinated axons in the distal nerve stump in the fibrin conduit group reached 86% of the nerve graft control and the weight of gastrocnemius and soleus muscles recovered to 82% and 89%, respectively. When a fibrin conduit was used to bridge a 20 mm sciatic nerve gap, the weight of gastrocnemius muscle reached only 43% of the nerve graft control. The morphology of the muscle showed a more atrophic appearance and the mean area and diameter of fast type fibres were significantly worse than those of the corresponding 10 mm gap group. In contrast, both gap sizes treated with nerve graft showed similar fiber size.

The combination of fibrin conduit with human MSC and daily injections of cyclosporine A enhanced the distance of regeneration by four fold and the area occupied by regenerating axons by three fold at 3 weeks after nerve injury and repair. In addition, the treatment also significantly reduced the ED1 macrophage reaction. At 12 weeks after nerve injury the treatment with cyclosporine A alone or cyclosporine A combined with hMSC induced recovery of the muscle weight and the size of fast type fibres to the control levels of the nerve graft group.

In summary, these results show that a BD hydrogel supplemented with rat Schwann cells can support the initial phase of neuronal regeneration across the conduit. The data also demonstrate an advantage of tubular fibrin conduits combined with human MSC to promote axonal regeneration and muscle recovery after peripheral nerve injury.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2012. , 55 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1518
Keyword [en]
Biosynthetic conduit, Mesenchymal stem cells, Nerve graft, Nerve tissue engineering, Peripheral nerve injury, Schwann cells
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-60915ISBN: 978-91-7459-476-8 (print)OAI: oai:DiVA.org:umu-60915DiVA: diva2:564572
Public defence
2012-11-27, BiA201, Biologihuset, Umeå Universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2012-11-06 Created: 2012-11-02 Last updated: 2012-11-08Bibliographically approved
List of papers
1. BD™ PuraMatrix™ peptide hydrogel seeded with Schwann cells for peripheral nerve regeneration
Open this publication in new window or tab >>BD™ PuraMatrix™ peptide hydrogel seeded with Schwann cells for peripheral nerve regeneration
2010 (English)In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 83, no 5, 207-213 p.Article in journal (Refereed) Published
Abstract [en]

This study investigated the effects of a membrane conduit filled with a synthetic matrix BD™ PuraMatrix™ peptide (BD) hydrogel and cultured Schwann cells on regeneration after peripheral nerve injury in adult rats. After sciatic axotomy, a 10mm gap between the nerve stumps was bridged using ultrafiltration membrane conduits filled with BD hydrogel or BD hydrogel containing Schwann cells. In control experiments, the nerve defect was bridged using either membrane conduits with alginate/fibronectin hydrogel or autologous nerve graft. Axonal regeneration within the conduit was assessed at 3 weeks and regeneration of spinal motoneurons and recovery of muscle weight evaluated at 16 weeks postoperatively. Schwann cells survived in the BD hydrogel both in culture and after transplantation into the nerve defect. Regenerating axons grew significantly longer distances within the conduits filled with BD hydrogel when compared with the alginate/fibronectin hydrogel and alginate/fibronectin with Schwann cells. Addition of Schwann cells to the BD hydrogel considerably increased regeneration distance with axons crossing the injury gap and entering into the distal nerve stump. The conduits with BD hydrogel showed a linear alignment of nerve fibers and Schwann cells. The number of regenerating motoneurons and recovery of the weight of the gastrocnemius muscle was inferior in BD hydrogel and alginate/fibronectin groups compared with nerve grafting. Addition of Schwann cells did not improve regeneration of motoneurons or muscle recovery. The present results suggest that BD hydrogel with Schwann cells could be used within biosynthetic conduits to increase the rate of axonal regeneration across a nerve defect.

Keyword
Peripheral nerve injury, Tissue engineering, Regeneration, Biomaterial, Retrograde labeling, Nerve repair
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-41350 (URN)10.1016/j.brainresbull.2010.07.001 (DOI)000284514300005 ()20633614 (PubMedID)
Available from: 2011-03-23 Created: 2011-03-23 Last updated: 2017-12-11Bibliographically approved
2. Biodegradable fibrin conduit promotes long-term regeneration after peripheral nerve injury in adult rats
Open this publication in new window or tab >>Biodegradable fibrin conduit promotes long-term regeneration after peripheral nerve injury in adult rats
2010 (English)In: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Vol. 63, no 11, 1893-1899 p.Article in journal (Refereed) Published
Abstract [en]

Peripheral nerve injuries are often associated with loss of nerve tissue and require autologous nerve grafts to provide a physical substrate for axonal growth. Biosynthetic neural conduits could be an alternative treatment strategy in such injuries. The present study investigates the long-term effects of a tubular fibrin conduit on neuronal regeneration, axonal sprouting and recovery of muscle weight following peripheral nerve injury and repair in adult rats. Sciatic axotomy was performed proximally in the thigh to create a 10-mm gap between the nerve stumps. The injury gap was bridged by using a 14-mm-long fibrin glue conduit, entubulating 2mm of the nerve stump at each end. A reversed autologous nerve graft was used as a control. The regenerative response from sensory and motor neurones was evaluated following retrograde labelling with Fast Blue fluorescent tracer. In control experiments, at 16 weeks following peripheral nerve grafting, 5184 (+/-574 standard error of mean (SEM)) sensory dorsal root ganglion neurones and 1001 (+/-37 SEM) spinal motor neurones regenerated across the distal nerve-graft interface. The fibrin conduit promoted regeneration of 60% of sensory neurones and 52% of motor neurones when compared to the control group. The total number of myelinated axons in the distal nerve stump in the fibrin-conduit group reached 86% of the control and the weight of gastrocnemius and soleus muscles recovered to 82% and 89% of the controls, respectively. The present results suggest that a tubular fibrin conduit can be used to promote neuronal regeneration following peripheral nerve injury.

Place, publisher, year, edition, pages
Elsevier, 2010
Keyword
Biosynthetic conduit, Dorsal root ganglion, Fluorescent tracer, Motor neurone, Nerve injury, Nerve graft
National Category
Neurosciences
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-35218 (URN)10.1016/j.bjps.2009.11.024 (DOI)000282944600034 ()20005193 (PubMedID)
Available from: 2010-08-10 Created: 2010-08-10 Last updated: 2017-12-12Bibliographically approved
3. Muscle recovery after repair of short and long peripheral nerve gaps using fibrin conduits
Open this publication in new window or tab >>Muscle recovery after repair of short and long peripheral nerve gaps using fibrin conduits
Show others...
2011 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 500, no 1, 41-46 p.Article in journal (Refereed) Published
Abstract [en]

Peripheral nerve injuries with loss of nervous tissue are a significant clinical problem and are currently treated using autologous nerve transplants. To avoid the need for donor nerve, which results in additional morbidity such as loss of sensation and scarring, alternative bridging methods have been sought. Recently we showed that an artificial nerve conduit moulded from fibrin glue is biocompatible to nerve regeneration. In this present study, we have used the fibrin conduit or a nerve graft to bridge either a 10 mm or 20 mm sciatic nerve gap and analyzed the muscle recovery in adult rats after 16 weeks. The gastrocnemius muscle weights of the operated side were similar for both gap sizes when treated with nerve graft. In contrast, muscle weight was 48.32 ± 4.96% of the contra-lateral side for the 10 mm gap repaired with fibrin conduit but only 25.20 ± 2.50% for the 20 mm gap repaired with fibrin conduit. The morphology of the muscles in the nerve graft groups showed an intact, ordered structure, with the muscle fibers grouped in fascicles whereas the 20 mm nerve gap fibrin group had a more chaotic appearance. The mean area and diameter of fast type fibers in the 20 mm gap repaired with fibrin conduits were significantly (P < 0.01) worse than those of the corresponding 10 mm gap group. In contrast, both gap sizes treated with nervegraft showed similar fiber size. Furthermore, the 10 mm gaps repaired with either nerve graft or fibrin conduit showed similar muscle fiber size. These results indicate that the fibrin conduit can effectively treat short nerve gaps but further modification such as the inclusion of regenerative cells may be required to attain the outcomes of nerve graft for long gaps.

Place, publisher, year, edition, pages
Amsterdam: , 2011
Keyword
autograft; biosynthetic conduit; muscle fiber; nerve injury; regeneration
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-42426 (URN)10.1016/j.neulet.2011.06.002 (DOI)
Available from: 2011-04-07 Created: 2011-04-07 Last updated: 2017-12-11Bibliographically approved
4. Fibrin conduit supplemented with human mesenchymal stem cells and immunosuppressive treatment enhances regeneration after peripheral nerve injury
Open this publication in new window or tab >>Fibrin conduit supplemented with human mesenchymal stem cells and immunosuppressive treatment enhances regeneration after peripheral nerve injury
Show others...
2012 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 516, no 2, 171-176 p.Article in journal (Refereed) Published
Abstract [en]

To address the need for the development of bioengineered replacement of a nerve graft, a novel two component fibrin glue conduit was combined with human mesenchymal stem cells (MSC) and immunosupressive treatment with cyclosporine A. The effects of MSC on axonal regeneration in the conduit and reaction of activated macrophages were investigated using sciatic nerve injury model. A 10mm gap in the sciatic nerve of a rat was created and repaired either with fibrin glue conduit containing diluted fibrin matrix or fibrin glue conduit containing fibrin matrix with MSC at concentration of 80×10(6)cells/ml. Cells were labeled with PKH26 prior to transplantation. The animals received daily injections of cyclosporine A. After 3 weeks the distance of regeneration and area occupied by regenerating axons and ED1 positives macrophages was measured. MSC survived in the conduit and enhanced axonal regeneration only when transplantation was combined with cyclosporine A treatment. Moreover, addition of cyclosporine A to the conduits with transplanted MSC significantly reduced the ED1 macrophage reaction.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
Peripheral nerve injury, Nerve conduit, Bone marrow, Mesenchymal stem cells, Regeneration
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-53882 (URN)10.1016/j.neulet.2012.03.041 (DOI)000304520300002 ()22465323 (PubMedID)
Available from: 2012-04-04 Created: 2012-04-04 Last updated: 2017-12-07Bibliographically approved
5. Long-term effects of fibrin conduit with human mesenchymal stem cells and immunosuppression after peripheral nerve repair in a xenogenic model
Open this publication in new window or tab >>Long-term effects of fibrin conduit with human mesenchymal stem cells and immunosuppression after peripheral nerve repair in a xenogenic model
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-60908 (URN)
Available from: 2012-11-02 Created: 2012-11-01 Last updated: 2012-11-08Bibliographically approved

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