Review Article

Effect of Electrical Stimulation on Ocular Cells: A Means for Improving Ocular Tissue Engineering and Treatments of Eye Diseases

Table 1

A brief description of the in vitro and in vivo studies on the effect of ES on the ocular cells.

SourceCellES patternOutcomeStudy typeRef

RatMCBiphasic pulses, duration, 1 ms; frequency, 20 Hz; current, 10 mA, for 30 min.(i) Upregulation of total BDNF (increase in intracellular but not in extracellular amounts)
(ii) Induction was dependent on calcium influx through L-VDCCs
(iii) The ES of MC may be applicable for BDNF demands of the retina.
In vitro[30]
RGCs
MC
TCES, biphasic current pulses 100 μA, 20 Hz, 0 to 3 ms/phase for 1 h.(i) Upregulation of IGF-1
(ii) IGF-1 appearance was first recognized in the endfeet of MC and then distributed into the inner retina.
(iii) The degree of rescue depended on the strength of the electric charge.
(iv) TCES revives the RCGs by increasing IGF-1 levels by MC.
In vivo[31]
Retinal cell
MC
TCES, 300 μA, 20 Hz, 3 ms/phase for \ 1 h, every 3 d after exposure to light for up to 14 d.(i) Upregulation of Bcl-2, CNTF, and BDNF.
(ii) Downregulation of Bax.
(iii) Upregulation of Bcl-2 and CTNF in MC.
(iv) The rate of reviving depended on the strength of the electric charge.
(v) TCES activates the intrinsic survival system by upregulation of antiapoptotic genes and downregulation of proapoptotic genes. Thus, prevents or delays photoreceptor degeneration.
In vivo[32]
MC1 ms pulse (20 Hz, 0–10 mA), continuous treatment for 30 min(i) Upregulation of FGF-2 messenger RNA and protein.
(ii) ES upregulates the production of FGF-2 in retinal Mueller cells.
In vitro[33]
MCBiphasic pulses, duration, 1 ms; frequency, 20 Hz; current, 0–10 mA, for 30 min.(i) Upregulation of IGF-1 transcription through the function of L-type Ca2+ channels and Ca2+ influx.
(ii) Downregulation of IGF-1 protein production.
(iii) TES induces IGF-1 production in cultured MC.
In vitro[34]
MGC
MC
3 ms biphasic pulses, 20 Hz, 300–1600 μA, continuous treatment for 1 h(i) Decrease activated microglia cells with ameboid shapes.
(ii) Increased reactive MC.
(iii) Inhibits IL-1β and TNF-α in microglia cells.
(iv) Positive regulative effect on the production of BDNF and CNTF in MC.
(v) ES is considered for delaying the progression of photoreceptor degeneration.
In vitro[35]

MurineRho−/− MCOne or two sessions of trans-palpebral ES or sham treatments for 7 consecutive days (4 spots on eyelids, 100 μA for 40 s)(i) ES directly stimulated cell proliferation and the expression of progenitor cell markers in MC cultures, via bFGF signaling.
(ii) ES might have a regenerative potential by releasing bFGF release and inducing MC proliferation and progenitor cell properties.
In vivo and in vitro[36]
RPC (postnatal day 1, green fluorescent protein+)100 μA pulse, (5 s duration, 1/min for 4 days)(i) Higher levels of the early photoreceptor marker CRX and PKC
(ii) Significantly lower levels of GFAP.
(iii) Pronounced neuronal morphologies with significantly longer dendritic processes and larger cell bodies.
(iv) ES has a possible role in directing progenitor cells toward differentiation.
In vitro[37]
RPC (postnatal day 1, green fluorescent protein+)Monophasic 5 V square-wave pulses (1 ms duration for 100 ms, 3 s bursts, 1/min, for 3 days)(i) Lower levels of N-cadherin.
(ii) Comparable levels of Cdc42.
(iii) Higher levels of ßIII-tubulin.
(iv) Oscillating calcium influxes
(v) Increasing neural differentiation
(vi) Activity-dependent dendritic morphogenesis toward early functional morphology.
(vii) ES directed RPCs toward developing functional properties.
In vitro[38]
CEC (Pax6+/− vs. Pax6+/+)200 mV/mm for 2 h(i) Pax6+/+ cells: cathodally migration. Upregulation of cathodal pSrc activity and total levels.
(ii) Pax6+/− cells: response to ES in speed and displacement changes but no significant in direction variation. No changes with pSrc.
(iii) ES causes cell migration and it depends on the level of Src signaling.
In vitro[39]

RabbitCECTranscutaneous ES (continuous DC electric field, 100 mV/mm, 30 min)(i) TCES elevated the rate of corneal healing mostly in the first 24 hIn vivo[40]
CEC
CSF
-4 V/cm for CEC
-6 V/cm for CSF
For a duration of 20, 50 min, 4 h
(i) After 20 min
(ii) Formation of spindle-shaped cells
(iii) Galvanotropism
(iv) After 50 min
(v) Migration of epithelial cells toward the cathode.
(vi) Migration of stromal fibroblasts toward the anode.
(vii) After 4 h
(viii) Treatment with caused cellular damage.
(ix) ES is responsible for corneal cell migration.
In vitro[41]

BovineCEC100-250 mV/mm for 5 h.(i) 10% FBS medium: significant galvanotropism, reorienting toward electric field vector, threshold .
(ii) FBS-free medium: no reorientation occurred until 250 mV/mm.
(iii) FBS-free medium + EGF, bFGF, or TGF-b1 (singly or in combination): significant cathodal galvanotropism at low field strengths.
(iv) Combination of growth factors and ES increases cell migration.
In vitro[42]

HumanCEC0–150 mV/mm for 3 h at 37°C(i) Upregulation of MMP3.
(ii) ES benefits from MMPs for applying on cell migration.
(iii) ES improved directional (cathodal) collective cell migration.
In vitro[43]
CEC100 mV/mm DC field, the current remains below 0.6 mA, at 37°C, for 1 h(i) Directed (cathodal) migration of CECs.
(ii) This migration is similar to keratinocytes, but faster.
(iii) ES plays an important role in human corneal wound healing.
In vitro[44]
Primary vs. transformed CEC100–250 mV/mm, 2-5 h(i) Both types had cathodal directed migration
(ii) Reorientation and directional migrations were voltage and serum dependent.
(iii) EGF facilitates cell migration.
(iv) Transformed human cells needed higher ESs (250 mV/mm) to show guided migration.
(v) ES might affect cell morphologies and directed cell migration in the healing process.
In vitro[45]

A: ampere; Bax: Bcl-2-associated X; Bcl-2: B-cell lymphoma 2; BDNF: brain-derived neurotrophic factor; Cdc42: cell division control protein 42 homolog; CEC: corneal epithelial cell; CNTF: ciliary neurotrophic factor; CRX: cone-rod homeobox; CSF: corneal stromal fibroblasts; EF: electric field; EGF: epidermal growth factor; ES: electrical stimulation; FBS: fetal bovine serum; FGF: fibroblast growth factor; GFAP: glial fibrillary acidic protein; h: hour; IGF: insulin-like growth factor; IL: interleukin; L-VDCCs: L-type voltage-dependent calcium channels; MC: Müller cell; MGC: microglia cell; min: minute; MMP: matrix metalloproteinases; Pax6: paired box protein; PKC: protein kinase-C; RGC: retinal ganglion cell; RPC: retinal progenitor cell; s: second; TCES: transcorneal electrical stimulation; TNF-α: tumour necrosis factor alpha; V: volt.