Heterologous fibrin sealant potentiates axonal regeneration after peripheral nerve injury with reduction in the number of suture points

Leite, Ana Paula; Pinto, Carina Guidi; Tibúrcio, Felipe Cantore; Sartori, Arthur Alves; Rodrigues, Antônio de Castro; Barraviera, Benedito; Ferreira, Rui Seabra; Filadelpho, André Luís; Matheus, Selma Maria Michelin

doi:10.1016/j.injury.2019.03.027

Cited by 24 publications

(24 citation statements)

References 57 publications

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“…As showed by immuno uorescence, canine AdMSC in co-localization with the BDNF, GDNF and p75 NTR indicates that the persistence of viable cells into the the microenvironment of lesion was crucial for the neurotrophic factor maintenance released by the cells. Previous studies showed that the use of HFB for reimplantation of ventral nerve roots lesioned or end-to-end nerve cooptation, proved cell support capacity, adhesion for axonal regeneration and neuroprotection [40][41][42][43][44][45][46].…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we used a scaffold composed of heterologous brin biopolymer (HFB) with adhesive and sealant properties to maintain canine AdMSCs in the local of lesion and to improve their therapeutic potential [38][39][40][41]. Recent studies have shown the ability to this brin to adhere and support the regeneration in the spinal cord and ventral and dorsal roots injuries in experimental models [42][43][44][45][46]. We hypothesized that the multi-functionalization of PCL-NGCs manufactured by 3D printing with canine AdMSCs embedded in brin biopolymer can enhance nerve regeneration following the repair of critical nerve injury in rats.…”

Section: Introductionmentioning

confidence: 99%

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3D-printed Nerve Guidance Conduits Multi-functionalized with Canine Multipotent Mesenchymal Stromal Cells Promote Neuroregeneration after Sciatic Nerve Injury in Rats

Rodríguez-Sánchez

Pinto

Cartarozzi

et al. 2020

Preprint

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Background: Nerve injuries are debilitating, leading to long-term motor deficits. Remyelination and axonal growth are supported and enhanced by growth factor and cytokines. Combination of nerve guidance conduits (NGCs) with adipose-tissue-derived multipotent mesenchymal stromal cells (AdMSCs) has been performing promising strategy for nerve regeneration.Methods: 3D-printed polycaprolactone (PCL)-NGCs were fabricated. Wistar rats subjected to critical sciatic nerve damage (12-mm gap) were divided into sham, autograft, PCL (empty NGC), and PCL+MSC (NGC multi-functionalized with 106 canine AdMSC embedded in heterologous fibrin biopolymer) groups. In vitro, the cells were characterized and directly stimulated with interferon-gamma to evaluate their neuroregeneration potential. In vivo, the sciatic and tibial functional indices were evaluated for 12 weeks. Gait analysis and nerve conduction velocity were analyzed after 8 and 12 weeks. Morphometric analysis was performed after 8 and 12 weeks following lesion development. Real-time PCR was performed to evaluate the neurotrophic factors BDNF, GDNF, and HGF, and the cytokines IL-6 and IL-10. Immunohistochemical analysis for the p75NTR neurotrophic receptor, S100, and neurofilament was performed with the sciatic nerve.Results: The inflammatory environment in vitro have increased the expression of neurotrophins BDNF, GDNF, HGF, and IL-10 in canine AdMSCs. Nerve guidance conduits multi-functionalized with canine AdMSCs embedded in HFB improved functional motor and electrophysiological recovery compared with PCL group after 12 weeks. However, the results were not significantly different than those obtained using autografts. These findings were associated with a shift in the regeneration process towards the formation of myelinated fibers. Increased immunostaining of BDNF, GDNF, and growth factor receptor p75NTR was associated with the upregulation of BDNF, GDNF, and HGF in the spinal cord of the PCL+MSC group. A trend demonstrating higher reactivity of Schwann cells and axonal branching in the sciatic nerve was observed, and canine AdMSCs were engrafted at 30 days following repair.Conclusions: 3D-printed NGCs multi-functionalized with canine AdMSCs embedded in heterologous fibrin biopolymer as cell scaffold exerted neuroregenerative effects. Our multimodal approach, support the trophic microenvironment, resulting in a pro-regenerative state after critical sciatic nerve injury in rats.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

3D-printed Nerve Guidance Conduits Multi-functionalized with Canine Multipotent Mesenchymal Stromal Cells Promote Neuroregeneration after Sciatic Nerve Injury in Rats

Rodríguez-Sánchez

Pinto

Cartarozzi

et al. 2020

Preprint

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“…The most recent study on nerve reconstruction by Leite et al [66] validated the use of the fibrin sealant as improvement to suture in sciatic repair, where a protective effect at the lesion site due to the use of HFS was observed.…”

Section: Discussionmentioning

confidence: 99%

Unique heterologous fibrin biopolymer with hemostatic, adhesive, sealant, scaffold and drug delivery properties: a systematic review

Buchaim

Cassaro

Shindo

et al. 2019

J. Venom. Anim. Toxins incl. Trop. Dis

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Fibrin biopolymers, previously referred as "fibrin glue" or "fibrin sealants", are natural biomaterials with diverse applications on health. They have hemostatic, adhesive, sealant, scaffold and drug delivery properties and have become widely used in medical and dental procedures. Historically, these biomaterials are produced from human fibrinogen and human or animal thrombin, and the possibility of transmission of infectious diseases by human blood is not ruled out. In the 1990s, to overcome this problem, a new heterologous biomaterial composed of a thrombin-like enzyme purified from Crotalus durissus terrificus venom and a cryoprecipitate rich in fibrinogen extracted from buffaloes Bubalus bubalis blood has been proposed. Therefore, a systematic review of studies on exclusively heterologous fibrin sealants published between 1989 and 2018 was carried out using the following databases: PubMed, SciELO and Google Scholar. The keyword used was "heterologous fibrin sealant". The search resulted in 35 scientific papers in PubMed, four in SciELO and 674 in Google Scholar. After applying the inclusion/exclusion criteria and complete reading of the articles, 30 studies were selected, which formed the basis of this systematic review. It has been observed that the only completely heterologous sealant is the one produced by CEVAP/UNESP. This heterologous biopolymer is proven effective by several studies published in refereed scientific journals. In addition, clinical trials phase I/II for the treatment of chronic venous ulcers authorized by the Brazilian Health Regulatory Agency (ANVISA) were completed. Preliminary results have indicated a safe and promising effective product. Phase III clinical trials will be proposed and required to validate these preliminary findings.

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“…In this study, we used a scaffold composed of heterologous fibrin biopolymer (HFB) derived from snake venom (i.e., Crotalus durissus terrificus ) that is non-cytotoxic, biodegradable with adhesive and sealant properties to retain the AdMSCs into the internal wall of the NGC [ 38 – 41 ]. In vivo, the HFB provided adequate adhesion of rootlets after lesioning in rodents [ 42 – 46 ]. We hypothesized that the multi-functionalization of PCL-NGCs manufactured by 3D printing with canine AdMSCs embedded in fibrin biopolymer can enhance nerve regeneration following the repair of critical nerve injury in rats.…”

Section: Introductionmentioning

confidence: 99%

3D-printed nerve guidance conduits multi-functionalized with canine multipotent mesenchymal stromal cells promote neuroregeneration after sciatic nerve injury in rats

et al. 2021

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Background Nerve injuries are debilitating, leading to long-term motor deficits. Remyelination and axonal growth are supported and enhanced by growth factor and cytokines. Combination of nerve guidance conduits (NGCs) with adipose-tissue-derived multipotent mesenchymal stromal cells (AdMSCs) has been performing promising strategy for nerve regeneration. Methods 3D-printed polycaprolactone (PCL)-NGCs were fabricated. Wistar rats subjected to critical sciatic nerve damage (12-mm gap) were divided into sham, autograft, PCL (empty NGC), and PCL + MSCs (NGC multi-functionalized with 106 canine AdMSCs embedded in heterologous fibrin biopolymer) groups. In vitro, the cells were characterized and directly stimulated with interferon-gamma to evaluate their neuroregeneration potential. In vivo, the sciatic and tibial functional indices were evaluated for 12 weeks. Gait analysis and nerve conduction velocity were analyzed after 8 and 12 weeks. Morphometric analysis was performed after 8 and 12 weeks following lesion development. Real-time PCR was performed to evaluate the neurotrophic factors BDNF, GDNF, and HGF, and the cytokine and IL-10. Immunohistochemical analysis for the p75NTR neurotrophic receptor, S100, and neurofilament was performed with the sciatic nerve. Results The inflammatory environment in vitro have increased the expression of neurotrophins BDNF, GDNF, HGF, and IL-10 in canine AdMSCs. Nerve guidance conduits multi-functionalized with canine AdMSCs embedded in HFB improved functional motor and electrophysiological recovery compared with PCL group after 12 weeks. However, the results were not significantly different than those obtained using autografts. These findings were associated with a shift in the regeneration process towards the formation of myelinated fibers. Increased immunostaining of BDNF, GDNF, and growth factor receptor p75NTR was associated with the upregulation of BDNF, GDNF, and HGF in the spinal cord of the PCL + MSCs group. A trend demonstrating higher reactivity of Schwann cells and axonal branching in the sciatic nerve was observed, and canine AdMSCs were engrafted at 30 days following repair. Conclusions 3D-printed NGCs multi-functionalized with canine AdMSCs embedded in heterologous fibrin biopolymer as cell scaffold exerted neuroregenerative effects. Our multimodal approach supports the trophic microenvironment, resulting in a pro-regenerative state after critical sciatic nerve injury in rats.

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Heterologous fibrin sealant potentiates axonal regeneration after peripheral nerve injury with reduction in the number of suture points

Cited by 24 publications

References 57 publications

3D-printed Nerve Guidance Conduits Multi-functionalized with Canine Multipotent Mesenchymal Stromal Cells Promote Neuroregeneration after Sciatic Nerve Injury in Rats

3D-printed Nerve Guidance Conduits Multi-functionalized with Canine Multipotent Mesenchymal Stromal Cells Promote Neuroregeneration after Sciatic Nerve Injury in Rats

Unique heterologous fibrin biopolymer with hemostatic, adhesive, sealant, scaffold and drug delivery properties: a systematic review

3D-printed nerve guidance conduits multi-functionalized with canine multipotent mesenchymal stromal cells promote neuroregeneration after sciatic nerve injury in rats

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