An integrated microfluidic device for screening the effective concentration of locally applied tacrolimus for peripheral nerve regeneration

Yin, Baosheng; Li, Ming; Liu, Bo-Ming; Wang, Shouyu; Zhang, Weiguo

doi:10.3892/etm.2014.2082

Cited by 14 publications

(6 citation statements)

References 20 publications

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“…FK506 results in the dissociation of p23 from Hsp90 within a steroid receptor complex, which activates neurite outgrowth (Pratt, ). Beside its neurotrophic properties, FK506 can locally stimulate Schwann cell proliferation (Yin et al, ). FK506 can also promote peripheral nerve regeneration through reducing scar formation (Que et al, ); however, little is known about the mechanism of this action.…”

Section: Resultsmentioning

confidence: 99%

A novel polymeric drug delivery system for localized and sustained release of tacrolimus (FK506)

Tajdaran

Shoichet

Gordon

et al. 2015

Biotech & Bioengineering

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Despite substantial improvement in microsurgical techniques for nerve repair, recovery after peripheral nerve injury is usually incomplete. FK506, an FDA approved immunosuppressant, improves functional recovery and reinnervation following peripheral nerve injury in animal models. However, systemically delivered FK506 causes undesirable global immunosuppression. We have, therefore, engineered a biodegradable local delivery system for FK506 using fibrin gel as a drug reservoir that could be placed at a site of nerve injury. FK506 was incorporated into fibrin gel in solubilized, particulated, and poly(lactic-co-glycolic) acid (PLGA) microspheres-encapsulated forms. A tunable release of FK506 in the fibrin gel from days to weeks was observed with the rate of release being most rapid for the solubilized form and then the particulate form. The most prolonged period of release was seen with the PLGA microsphere-encapsulated form. As analyzed by in vitro dorsal root ganglion (DRG) neurite extension assay, PLGA microsphere encapsulation of FK506 did not alter the drug's properties and the released FK506 maintained its bioactivity over the entire period of release. This study suggests that local delivery of FK506 with fibrin hydrogel could be used to enhance peripheral nerve regeneration.

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Section: Resultsmentioning

confidence: 99%

A novel polymeric drug delivery system for localized and sustained release of tacrolimus (FK506)

Tajdaran

Shoichet

Gordon

et al. 2015

Biotech & Bioengineering

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“…The determination of drug concentration in microfluidic GCC was based on the flow field distribution. 60 , 61 The CGC zone deployed zigzag design so as to mix different medium from inputs sufficiently. Crystal violet and PBS were used to establish varying drug concentrations that could be reflected by the color depth of crystal violet.…”

Section: Methodsmentioning

confidence: 99%

Kinsenoside screening with a microfluidic chip attenuates gouty arthritis through inactivating NF-κB signaling in macrophages and protecting endothelial cells

et al. 2016

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Gouty arthritis is a rheumatic disease that is characterized by the deposition of monosodium urate (MSU) in synovial joints cause by the increased serum hyperuricemia. This study used a three-dimensional (3D) flowing microfluidic chip to screen the effective candidate against MSU-stimulated human umbilical vein endothelial cell (HUVEC) damage, and found kinsenoside (Kin) to be the leading active component of Anoectochilus roxburghi, one of the Chinese medicinal plant widely used in the treatment of gouty arthritis clinically. Cell viability and apoptosis of HUVECs were evaluated, indicating that direct Kin stimulation and conditioned medium (CM) from Kin-treated macrophages both negatively modulated with MSU crystals. Additionally, Kin was capable of attenuating MSU-induced activation of nuclear factor-κB/mitogen-activated protein kinase (NF-κB/MAPK) signaling, targeting IκB kinase-α (IKKα) and IKKβ kinases of macrophages and influencing the expressions of NF-κB downstream cytokines and subsequent HUVEC bioactivity. Inflammasome NLR pyrin domain-containing 3 (NALP3) and toll-like receptor 2 (TLR2) were also inhibited after Kin treatment. Also, Kin downregulated CD14-mediated MSU crystals uptake in macrophages. In vivo study with MSU-injected ankle joints further revealed the significant suppression of inflammatory infiltration and endothelia impairment coupled with alleviation of ankle swelling and nociceptive response via Kin treatments. Taken together, these data implicated that Kin was the most effective candidate from Anoectochilus roxburghi to treat gouty arthritis clinically.

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“…In addition, the interaction of FK506 with other cell targets at the growth cone level such as Schwann cells (SCs), could promote neurite extension. FK506 has been shown to promote SC proliferation in vitro (Fansa et al, ; Yin, Li, Liu, Wang, & Zhang, ). An investigation of the upregulation of the factors that are released from SCs after FK506 local concentration to neurites could elucidate the mechanism of action of FK506 that promotes neurite extension and increases neurite density after the local FK506 delivery.…”

Section: Discussionmentioning

confidence: 99%

Local FK506 dose‐dependent study using a novel three‐dimensional organotypic assay

Tajdaran

Chan

Zhang

et al. 2018

Biotech & Bioengineering

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Local administration of FK506, an FDA approved immunosuppressant with neuroregenerative properties, is a promising technique to achieve improved peripheral nerve regeneration while preventing the side effects associated with the systemic administration of this drug. Although considerable research has been devoted to the development of clinically suitable systems for local delivery of FK506 to the site of nerve injury and repair, the optimal dose of FK506 for enhancement of axon regeneration in the peripheral nerve has not yet been established. To this end, we devised a threedimensional (3D) organotypic assay capable of mimicking the peripheral nerve. This assay consisted of a neonatal rat dorsal root ganglion (DRG) extending its neurites into the native peripheral nerve scaffold provided by an acellular nerve allograft (ANA). A novel 3D compartmented cell culture system was adapted from the 3D organotypic assay to achieve local delivery of FK506 just to the growing neurites in vitro and establish the required local dose of FK506 for peripheral nerve regeneration. A bimodal dose response was observed by culturing the entire DRG-ANA construct with media containing different concentrations of FK506. Low drug concentration of 1 pg/ml and high drug concentration of 100 ng/ml lead to the longest neurite extension in vitro. Furthermore, regardless of the FK506 concentration, concentrating the drug to the growing neurites resulted in significant increase in both neurite extension and neurite density, an effect that was not observed with the FK506 delivery to both neurites and neural cell bodies within DRG. The findings in this study provide valuable insight into the optimal local dose of FK506 for peripheral nerve regeneration. Furthermore, for the first time, this study suggests the potential interaction of FK506 with axons at the level of the growth cone. K E Y W O R D S biomaterial, dose-dependent study, FK506, local drug delivery, organotypic assay, peripheral nerve regeneration, rat model, regenerative medicine 1 | INTRODUCTION After peripheral nerve injury, the expression of intrinsic growth factors and neurotrophic factors necessary for axon regeneration reduces with time and regeneration distances (Brushart et al.injured peripheral nerve with proteins and molecules that have neurotrophic and neuroregenerative properties such as brain-derived neurotrophic factor, glial-derived neurotrophic factor, and FK506 to compensate for reduced expression of the intrinsic factors, holds promise for enhancing Biotechnology and Bioengineering. 2019;116:405-414.wileyonlinelibrary.com/journal/bit

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An integrated microfluidic device for screening the effective concentration of locally applied tacrolimus for peripheral nerve regeneration

Cited by 14 publications

References 20 publications

A novel polymeric drug delivery system for localized and sustained release of tacrolimus (FK506)

A novel polymeric drug delivery system for localized and sustained release of tacrolimus (FK506)

Kinsenoside screening with a microfluidic chip attenuates gouty arthritis through inactivating NF-κB signaling in macrophages and protecting endothelial cells

Local FK506 dose‐dependent study using a novel three‐dimensional organotypic assay

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