Scope and Objectives

1. To develop a cost-effective microneedle array system for administration of medications/vaccines in the paediatric age group.
2. To evaluate the performance of the microneedle system in comparison to conventional needles.
3. To study a range of microneedle geometries and develop disposable microneedle device for paediatric application.
4. On the basis of the above results a microneedle array shall be developed for adult application.
5. To evaluate the performance of the developed micro needle array in terms of pressure, force, flow rate and quantifying the medications/vaccines to be delivered
6. To conduct animal studies for demonstrating safety and efficacy of the microneedle array.
7. To conduct human studies for demonstrating safety and efficacy of the microneedle array; and immunogenicity of vaccine(s) delivered through the microneedle array.
8. SASTRA will evaluate the needle array for transdermal in vitro and in vivo models

Deliverables

The project is to enable the cost-effective production of reliable disposable Microneedle array for the paediatric application. This will be achieved by the concurrent development of micro manufacturing techniques suitable for mass production. Three sets of microneedle with dimensions, results of functional tests and complete specifications will be delivered.

Videos

Scientific Output

1. SU8 is biocompatible negative photoresist polymer, that cures under exposure of UV light followed by application of heat. This property can be utilized for fabrication of microneedle array by UV exposure of photoresist layer through appropriately designed photomask. Typical process flow for fabrication of SU8 microstructures involves spin coating, baking, UV exposure, post exposure baking followed by chemical development. Protocol for fabrication of SU8 microneedles on glass substrate is developed.
2. Simulation model is developed to verify strength of SU8 microneedles for piercing into skin
3. Various micromolding techniques such as deposition, extrusion, replica molding, etc. are under exploration for fabrication of microneedles using different biocompatible polymer/ composite materials such as Urethane Methacrylate, PMMA, PLA, dental cement, biodegradable polymers. Various inhouse mold designs are being developed for achieving reliable micromolding
4. A microneedle patch by assembly of ground steel capillary tubes in array with protrusion control is proposed. Syringe fit-able adapter as shown is conceptualized. To realize this design, in house development of tooling and fixtures was done for grinding of stainless steel capillary tubes using CNC milling machine. These ground needles were then assembled into syringe fit-able acrylic adapter to realize microneedle patch.
5. With mass production as focus, attempt was made to obtain microneedles by rapid processing techniques such as punching. Microtools needed for punching were developed using electrochemical machining technique. 6. Animal trials conducted on guinea pigs at SASTRA university for signs of dermal toxicity as per the OECD 404 guidelines: Edema, Erythema, Eschar formation, Hyperkeratosis, Hyperplasia, Scaling, Wound formation, etc.

Results and outcome till date

1. SU8 solid microneedles successfully fabricated using optimized designed protocol. Simulation studies showed sufficient strength, which was in turn verified by compressive strength testing at UTM. Animal trials at SASTRA university showed no adverse reaction upon application of the patch.
2. Polymer microneedles were successfully fabricated using various micromolding techniques show sufficient strength on UTM testing. Skin piercing in rat skin was verified. Aspect ratio (needle ht/ tip diameter) as high as 45 achieved during by molding.
3. Syringe fitable adapters successfully fabricated and delivery verified in rat. Minor leakages observed. Design modifications to prevent leakage to be investigated further.
4. Various punching trials tried: Tungsten/ HSS tool with metal die, SS tool with rubber die, Rubber tool with metal die. Punching was tried at CNC machine, manual press, UTM, etc. All trials resulted in side opened cup instead of needle. Further investigation in this line discontinued.
5. Skin histopathological analysis show no significant inflammatory changes compared to normal skin for various polymer microneedle insertion.

Societal benefit and impact anticipated

Microneedles, tiny projections designed to break top layer of the skin can overcome molecular size limitations and improve drug penetration capability through skin. Further, needles are designed not to touch nerve endings into skin, hence drug delivery can be practically painless. Skin being the exposed organ of the body, possesses immunologically superior characteristics. Hence, vaccine delivery in skin (Intradermal vaccination) is expected to generate equivalent immune response to traditional methods of vaccination at much lower dose. Especially in India, where millions of children are required to be vaccinated annually, dose sparing capability of vaccination by intradermal route must be explored to dramatically reduce costs of mass vaccination programs. There is urgent need to identify alternate microneedle based system for delivering injectable medicines/vaccines. For the patients benefit, the drugs such as antibiotics should be delivered within the specific range of concentration between the maximum and minimum levels and also it should maintain the same level for longer period. Drug concentration above the maximum allowed level is toxic and below minimum level will have no therapeutic benefits. However, the conventional drug delivery method does not always make it feasible to deliver the drug effectively and accurately within the therapeutic range or window. There is a sharp initial increase in concentration followed by a fast decrease to a level below therapeutic level. Using microneedles and micropump based system, slow and sustained drug delivery to precise therapeutic level can be envisioned. Further, the microneedle-based platform can also extended for site-specific delivery of therapeutic entities to infants and adults for diseases such as arthritis, diabetes and cardiac disorders.

Next steps

1. Protocol developed for SU8 hollow microneedle fabrication. Process optimization currently in progress
2. Fixture for holding syringe to be developed for accurate dose control using syringe fitable adapter.
3. Large scale animal trials to be conducted using developed microneedles at PGI: Chandigarh, SASTRA university: Thanjavur and InStem: Bengaluru.

Publications and reports

Our research on simulation and fabrication of SU8 solid microneedle array has been presented as paper titled (Simulation, Fabrication and Characterization of SU8 solid microneedle array for transdermal drug delivery) in 3rd ISSE National Conference 2017, Chandigarh chapter held in October 2017.

Patents

Applied for patent on Mold design developed for fabrication of microneedles at IPTEL, IISc.

Scholars and Project Staff

Sukruth.S (Project Assistant) : from 01.04.2017 to 01.09.2018 2. Diwakar. S. Shastri (Project Assistant): from 17.07.17 to 02.07.2018. 3. Dr. Sriram.K (Research Associate) : from 17.07.2017 to 01.08. 2018 4. Geetha.S (Secretarial Assistant): from 01.04.2017 till date 5. Mahathy Rajagopalan (Project Assistant): from 02.11.2017 to 02.10.2018 6. Sumukha.V. Udupa (Project Assistant) : from 02.11.2017 to 02.10.2018 7. Dr. Suman Pahal (Research Associate) : from 01.08.2018 till date. 8. Dr. Nagarjuna Neella (Research Associate) : from 02.07.2018. till date. 9. Kedar Badnikar : PhD student.

Challenges faced

Each route contemplated for fabrication of microneedles needs detailed analysis of effect of different process parameters and corresponding outcomes. These analyses sometimes take longer time than expected. Sometimes even after long duration of contemplation useful results may not be obtained (like in Punching route of microneedle fabrication). Since our objective is to provide robust solution to the problem, multiple cycles of experiments for verifying obtained results are required. In microneedle molding methods, critical part for success of the method is Master Mold. While micromachined mold is possible to be developed at CMTI, cost-effectiveness is important challenge. This led to our effort in developing molds inhouse as per our requirements.

Other information