Emerging era of microneedle array for pharmaceutical and biomedical applications: recent advances and toxicological perspectives

Dugam, Shailesh; Tade, Rahul; Dhole, Rani; Nangare, Sopan

doi:10.1186/s43094-020-00176-1

Future Journal of Pharmaceutical Sciences

Table 4 In vivo and in vitro toxicity of MNs on a different model

From: Emerging era of microneedle array for pharmaceutical and biomedical applications: recent advances and toxicological perspectives

Sr. No.	Study	Observation	Toxicity effect	Result/inference	Ref.
MNs free from in vivo and in vitro toxicity
1.	The standard Draize skin irritation method was used to measure erythema and edema of the thiolated CS-MNs patch of tacrolimus.	After 1 h, the removal of thiolated CS-MNs loaded tacrolimus has increased erythema score.	No edema was exhibited	An elevated quantity of needles might cause these symptoms, which could be parallel to the increases in the number of pores per unit area of skin.	[140]
2.	A piece of rat dorsal skin was defrosted naturally, and then the curcumin micelle-loaded dissolvable composite MNs were inserted with the thumb using a force (5 N). Then MNs were removed after the insertion and the skin was exposed to trypan blue solution for 5 min.	The blue dot matrix was found on the surface of rat skin after being washed with a saline solution.	No any inflammation and irritation occurs	The dye could not penetrate the SC, but it can stain the inner tissue through the microholes generated in the skin layer.	[141]
3.	The hair on the back of each rat was shaved, and the aconitine loaded diethylene glycol monoethyl ether-mediated microemulsion assisted MNs was applied once daily for 7 consecutive days.	The cell morphology of each layer was found to be normal after the exhibition of the test.	No obvious irritant reaction and no inflammatory reaction were found.	Because of the microemulsion, the aconitine constant subcutaneous distribution obtained, which resulted in the diminishing the toxicity	[142]
4.	5-Fu loaded monomethoxy-poly(ethylene glycol)-polycaprolactone NPs integrated HA dissolvable MNs was evaluated for in vitro cytotoxicity by human epidermoid cancer cell line-A431 and the human melanoma cell line-A375 through MTT assay.	It was demonstrated the cell inhibition ability almost similar to 5-Fu and showed a better inhibition at 48 h.	MNs have exhibited no obvious cytotoxicity without NIR laser.	The monomethoxy-poly(ethylene glycol)-polycaprolactone can a good carrier for 5-Fu delivery.	[103]
5.	The gelatin methacryloyl and β-cyclodextrin (Gel-MA-β-CD) based MNs have penetrated the epidermal layer after 1 h of topical implantation.	No MN array-related damage or inflammation was found for up to 3 days.	No irritation and inflammation occur.	It showed biosynthetic Gel-MA-β-CD MN arrays were biocompatible with the skin and were potentially competent in sustained release of the drug.	[143]
6.	In this study, two amifostine-armored MNs patches have been topically administered on the shaved dorsal skin (12 h).	No noticeable weight loss	No toxicity and inflammation in the major organs were exhibited	It showed that amifostine-armored-MNs were a harmless technique used for active delivery.	[139]
7.	Acute skin irritation of 3 min treatment by the MTX-HA-dissolvable (MTX-HA) MNs was performed by using the dorsal skin of mice.	No erythema and swelling	No obvious irritative reaction	It increased the convenience and acceptability for frequent administration of drugs or active agent using the MNs technique.	[144]
8.	The cytotoxicity study of drug-free PEGDA/sucrose MNs was performed by human umbilical vein endothelial cells (HUEVCs) by MTT cell viability assay.	The cell viabilities were all above 90% at the 1:20, 2:20, and 3:20 mass ratio of (sucrose/PEGDA), which is significantly higher than the viability of those incubated with MNs made of pristine PEGDA or PEGDA plus fibrin scaffold.	No cytotoxic reaction occurs	It confirmed that PEGDA/ sucrose MNs exhibited good biocompatibility, particularly after the incorporation of sucrose in the needle matrix.	[98]
9.	The study was carried out by applying MNs (without drug) followed by NIR light irradiation.	No noticeable tissue lesion took place in this study.	No cytotoxic reaction and irritation occur.	It confirmed the hypo-toxicity and safety of as-fabricated MNs for potential clinical applications.	[72]
10.	The Ex4 tip-loaded MN arrays and subcutaneous injections were compared for their acute efficacy in type 2 diabetic GK/Slc rats.	The pores created by MNs were much greater (disappeared at 24 h after application) than the one pore created by subcutaneous injection (remained visible even at 72 h after).	No inflammation	It confirmed that MNs’ arrays did not cause serious skin damage or irritation, and they can be safe after application.	[145]
11.	The in vitro EpiDerm™ skin irritation experiment on the EPI-200-SIT (reconstructed human epidermal model EpiDerm) has been conducted to examine the irritancy level of vismodegib solution.	The skin irritation test showed that the vismodegib solution was non-irritant to the reconstructed human epidermal model EpiDerm.	No irritation occurs	It proved that vismodegib formulation could be used safely on animal skin with no irritation to the application side.	[18]
12.	The cytotoxicity of rapamycin- dissolving MNs were carried out on HUVECs, Cell counting Kit-8 assay.	The viability of HUVECs incubated vehicle dissolving MNs was higher than 80%.	No cytotoxicity	It showed the better biocompatibility of the dissolving MNs.	[19]
13.	The lipid bilayer-coated with antigen-loaded mSiO₂-NPs (LB-MSNOVA) for intradermal antigen delivery via coating MN arrays had tested for toxicity study.	The MNs can undergo hydrolysis to form a nontoxic by-product. The intravenously injected MNs were mainly excreted out of mice through urine and faces.	No cytotoxic reaction.	It shows that the developed MNs are biodegradable and safe for use.	[20]
MNs showed in vivo and in vitro toxicity
14.	The dissolving MNs patch was successively applied on depilated mice’s back skin and physiological saline the negative control	It was observed that the dissolving MNs containing β–sodium Glycerol-phosphate and hydroxypropyl β-cyclodextrin induced slight mechanical damage.	The histopathological tissue section was exhibited. The mild inflammation in the cell infiltration is seen in the dermis.	The skin irritation caused because of dissolving MNs has mild and transient.	[136]
15.	The mice group was transcutaneously treated with Ex4-loaded MN patch.	In this study, they induced the MNs patch administration and observed inflammatory reaction in comparison with intradermal injection of dual mineralized particles.	A slight inflammation reaction occurs	The less invasiveness of the MNs patch to the skin suggested that the Ex4-MNs patch is a highly biocompatible treatment.	[84]
16.	The skin irritation after the successful application of alendronate-loaded MN array was calculated using the Draize method.	At 24, the irritation score after the application of a blank MN array was not changed. Besides, the light erythema of the skin was observed 4 and 8 days after a 24 h application of a microneedle array.	Slight erythema and edema and irritation occurs	Further, studies are needed to improve the safety of alendronate-loaded MN array. In this study, alendronate-induced skin irritation can avoid by incorporating antioxidants in the alendronate MNs.	[21]

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