Microneedles: Just Deep Enough

Nov 1, 2008 | Contact Author | By: Angela R. Eppler, PhD; Wyeth Consumer Healthcare
Your message has been sent.
(click to close)
Contact the Author
This item has been saved to your library.
View My Library
(click to close)
Save to My Library
Title: Microneedles: Just Deep Enough
microneedlesx transdermalx microporationx skin perturbationx penetrationx
  • Article
  • Media
  • Keywords/Abstract

Keywords: microneedles | transdermal | microporation | skin perturbation | penetration

Abstract: Microneedle technology could, with supporting research, serve as a novel delivery system for personal care applications. Additionally, ingredients previously labeled as ineffective may find new life via this method, increasing the opportunity for skin care R&D.

Ask any child … one of the first things learned and never forgotten is that needles hurt; however, innovators in the dermal delivery arena have developed micron-sized needles that are long enough to effectively deliver a drug but short enough to eliminate the associated pain.1 Considerable research has been conducted to demonstrate the benefits of solid, hollow and dissolvable microneedles for medicinal applications such as insulin therapy2,3 and gene delivery.4 In addition, the use of transcutaneous needles for cosmetic improvements has grown during the past decade,5 suggesting their transition into the personal care market.

Transdermal Delivery

According to Cleary,6 enthusiasm flourished in the latter decades of the 20th century around transdermal drug delivery. Until this point, the main cornerstones of medicinal treatment were oral administration and intravenous injection. Hepatic and intestinal first pass metabolism challenged oral delivery, while parenteral delivery was invasive and painful. Transdermal drug delivery was developed with the expectation to establish a self-administered, pain-free and stable dosage form, suitable for localized or controlled systemic delivery. Unfortunately, the topical delivery of actives was impeded by a relatively impermeable barrier: the stratum corneum.6

Cleary continues by noting that transdermal delivery ultimately was limited to a small number of lipophilic drugs subject to passive transport through the skin, including: nitro- glycerin, fentanyl, nicotine and hormone replacements. By the late 1990s, the complexity of transdermal delivery turned the interest and funding of pharmaceutical companies to other directions. In the meantime, academia and the technology industry pursued on, along with the advancement of microelectronics. In the early 21st century, skin delivery re-emerged with active transport options including improved chemical penetration enhancers, liposome/encapsulation, thermal delivery, magnetophoresis, iontophoresis, sonophoresis and mechanical microporation, i.e., microneedles.6 

Microneedle R&D

The microneedle concept is based on physical skin perturbation as a means for delivery. Solid silicon and metal microneedles, as referenced by Lee et al.,7 were originally designed as a pre-step to topical application via patch or vehicle. By physically creating the transport channels, passively impermeable drugs could be delivered transdermally.

To improve simplicity and efficiency, microneedle surface coating was explored, in which the exterior of the microneedles are coated with a drug prior to dermal application for bolus delivery.9–11 In a study conducted by Oh et al.,12 three different microneedle delivery methods were evaluated. Results showed that the highest delivery rate was achieved when a topical gel was delivered with microneedles as opposed to its delivery either before or after their application.12 

A logical next step was hollow microneedles, which allow for more controlled delivery. Directed release, or delivery on command, can be achieved when hollow microneedles are used in conjunction with a pump system controlling a pressured reservoir.13 

According to Nordquist et al., hollow microneedles are a potential delivery system for insulin. In their study, the researchers evaluated an expandable liquid reservoir that could adjust microneedle delivery by means of controlled voltage. This method allows for both controlled delivery and dose adjustment for the patient. Tao et al.13 expressed that a closed loop system, in which a device can independently sample, analyze and respond to biological stimuli such as blood glucose levels, would be an ideal usage for microneedles.

An observation by Martanto et al.14 identified the need for slight needle retraction following insertion of hollow needles; when microneedles were inserted to a depth of 1,080 µm, then slightly retracted, delivery increased by a factor of 10. This effect has been attributed to skin deformation during insertion, thus resulting in compaction. By retracting the needles, the compaction can be alleviated, thereby encouraging fluid flow. 

Microneedles, either solid or hollow, pose an inherent safety risk of tip breakage during insertion or within the skin. Dissolvable microneedles made of polymers15 or sugar2, 16 circumvent this risk. According to Lee et al.,7 the needle can be loaded to deliver a specified bolus dose, whereas loading either the patch backing only or both the needles and the backing can achieve sustained release. Needles begin to dissolve within seconds after injection and sustained delivery can be achieved and controlled on the order of minutes to days.7 The backing layer reaches an equilibrium state while simultaneously dispensing drug and collecting interstitial fluid. This interstitial fluid can then be sampled as needed, which demonstrates an achievable inward and outward flux for dissolvable microneedles.7 

In addition to insulin, microneedles also are being researched as an effective means for delivery of large 

macromolecular drugs17 such as DNA. In a study conducted by Pearton et al., blunt-tipped needles were used as opposed to sharp-tipped needles since previous research demonstrated that more discernable microchannels were created using blunt tips. These channels were shown to be large enough for transport of large molecular drugs. 

Biodegradable polymeric solutions were used for gene delivery and designed in such a way that, once the solution reaches body temperature, it forms a gel that provides a sustained release effect. Microneedle arrays as small as 3 mm2 comprised of 16 microneedles were shown to provide effective delivery (see Figure 1 and Figure 2). 

In addition to hollow microneedle delivery, the delivery of insulin through dextrin microneedles has been examined.2 Dextrin creates a self-dissolving, biodegradable microneedle and in vitro studies showed that almost the entire dose was delivered within an hour. No change in the time profile was observed with a decrease in needle quantity. In comparison with intra-venous delivery, bioavailability ranged from 91.3% (@ 2.5 IU/kg) to 97.7% (0.5 IU/kg). The stability of the insulin dextrin microneedles upon storage at -80°C, 20°C and 40°C for one month was determined to be 98.2%, 98.9% and 99.0% of initial dose levels, respectively. In vivo microneedle delivery of Evans Blue, a model dye for insulin, visually supported the predicted clearance of insulin from the epidermis to the trans cutaneous tissue resulting in systemic absorption. The channels created by the dissolving microneedles scabbed at 24 hr and cured at 72 hr.2

Optimization Factors

Dissolvable microneedles are designed with a delicate matrix that enables their dissolvability while maintaining enough mechanical strength to allow for insertion.7 Maltose microneedles, as examined by Kolli et al.,16 were found to dissolve quicker than polymer microneedles. Additionally, the highly ordered molecular arrangement of crystalline maltose assists in providing structure during the microneedle fabrication. Unfortunately, to maintain the delicate matrix balance, only a small amount of drug can be incorporated into this type of microneedle. 

Delivery through microneedles is more complex than solid, hollow or dissolvable; and bolus or sustained release. Microneedles come in various shapes and sizes—i.e., length (μm), conical and pyramidal7—and they can deliver from the outer surface, hollow bores or side openings. Analysis of three microneedle arrays of varying densities (45, 99, and 154 microneedles/cm2) confirmed that the higher the microneedle density, the greater the absorption.12 

Roxhead et al.18 expressed the need for a closed-package microneedle system in order to protect the integrity of the deliverable active (i.e., maintain concentration, minimize degradation). A thin gold membrane over the microneedle opening can create a leak-proof seal, as confirmed by evaporation testing. These seals were shown to break during insertion; however, biocompatibility of these materials with the skin is still being investigated.18 Additionally, Verbaan et al. recently showed that the impact insertion method (manual vs. electric) can have a significant effect on microneedle efficiency. 

Wang et al.19 concluded that in addition to the microneedle structure, factors such as formulation, wear time and system/patch size can all be influential. 

Cosmetic Application

With opportunities for the microneedledelivery system increasing in the medical field, the personal care industry may expect to see an influx of this type of delivery system into the market. Both Park15 and Kolli,16 et al., have demonstrated simple and inexpensive means to manufacture microneedles, assisting their movement into mass production.

Needle dermabrasion was described in 1997 by Camirand and Doucet20 for its ability to improve scars. And currently, mesotherapy—a treatment used in cosmetic dermatology involving the injection of bioactive substances through dermal multipunctures—is growing globally in popularity to treat photoaged skin, among other uses.21 

A limited number of companies currently market needle rollers, while an increasing number of patents worldwide recognize microneedles for cosmetic purposes. These devices that were once limited to medical professionals are now available to spa and skin care professionals as well as the personal user for at-home improvement of wrinkles and large pores. However, recommended needle depth varies from 0.25 mm for the personal user to 2.2 mm for medical purposes.22  

Commercially marketed needle rollers are available for a range of cosmetic purposes, from increasing penetration of topically applied creams23 to improving skin pigmentation and treating cellulite.24 Topical treatments referenced for use with skin needle rollers include: hair re-growth formulas,25 vitamins26 and peptides.24 An example of an anti-wrinkle peptide formula marketed in combination with a needle roller lists the following composition: water (aqua); acetyl hexapeptide-8, 15%; palmitoyl-pentapeptide 3, 5%; EGF, 0.001%; adenosine, 0.04%; hyaluronic acid, 0.001%; hydrolyzed DNA, 0.00001%; hydrolyzed RNA, 0.00001%; hydroxyethylcellulose, 0.25%; and diazolidinyl urea, 0.25%.24

In regard to safety, needle roller marketers recommend similar safety precautions such as limiting use to a single individual, replacing the roller approximately every six months, and storage of the needle roller in a protective case. A few companies offer sterilizing solutions for use between treatments.24

As technology continues to progress, safety concerns ultimately arise. Some research labs have immobilized further pursuit of this technology due to expressed safety concerns about the entry of undesired entities such as preservatives, irritants and microorganisms. 27 Meanwhile, others suggest that further research could be conducted to minimize these risk factors, such as reducing the microneedle diameter size to the point that bacterial entry is limited.28 Currently, the US Food and Drug Administration is addressing scientific issues, as stated in the July 25, 2007, Nanotechnology Task Force Report, surrounding interactions with biological systems and safety and quality testing approaches for nanoparticles.29 As microneedle technology advances, it too could become vulnerable to similar scrutiny.


The personal care window of opportunity no longer stops at the skin’s surface.30 To address elevated consumer expectations, advancements in delivery systems and ingredients must be implemented.31 An identified unmet need exists for advanced at-home skin care that is minimally invasive with negligible discomfort.32 With supporting research, microneedle technology could assert its position as a novel delivery system in personal care. Additionally, ingredients previously labeled ineffective may find new life via this delivery method, thereby exponentially increasing the opportunity for skin care R&D.31 As medical research continues to develop microneedle technology, so too will it develop applicable uses, associated markets and potential regulatory constraints. In keeping with tradition, science that begins in the pharmacy ends in the department store.30


1. FJ Verbaan et al, Improved piercing of microneedle arrays in dermatomed human skin by an impact insertion method, J of Controlled Release 128 80–88 (2008)

2. Y Ito et al, Feasibility of microneedles for percutaneous absorption of insulin, Eur J of Pharm Sciences 29 82–88 (2006)

3. L Nordquist et al, Novel microneedle patches for active insulin delivery are efficient in maintaining glycaemic control: An initial comparison with subcutaneous administration, Pharm Research 7 1381–1388 (Jul 24, 2007) 

4. M Pearton et al, Gene delivery to the epidermal cells of human skin explants using micro-fabricated microneedles and hydrogel formulations, Pharm Research 2 407–416 (Feb 25, 2008)

5. B Glauber and B Poston, Face of America has a lot of Botox: Census snapshot shows we pursue youth, new things, The Columbus Dispatch (Dec 21, 2007), available online at: www.dispatch.com (accessed Jun 25, 2008) 

6. GW Cleary, Transdermal and transdermal-like delivery system opportunities: Today and the future, Drug Delivery Technology 3(5) 34–40 (Jul–Aug 2003)

7. JW Lee, JH Park and MR Prausnitz, Dissolving microneedles for transdermal drug delivery, Biomaterials 29 2113–2124 (2008)

8. DP Wermeling et al, Microneedles permit transdermal delivery of a skin-impermeant medication to humans, PNAS 105(6) 2058–2063 (Feb 2008)

9. M Cormier et al, Transdermal delivery of desmopressin using a coated microneedle array patch system, J of Controlled Release 97 503–511 (2004)

10. HS Gill and MR Prausnitz, Coated Micro-needles for transdermal delivery, J of Controlled Release 117 227–237 (2007)

11. HS Gill and MR Prausnitz, Coating Formulations for Microneedles, Pharm Research 7 1369–1380(Jul 2007)

12. JH Oh et al, Influence of the delivery systems using a microneedle array on the permeation of a hydrophilic molecule, calcein, Eur J of Pharm Biopharm, 9 (3) 1040–1045 (Aug 2008) 

13. SL Tao and TA Desai, Microfabricated drug delivery systems: From particles to pores, Adv Drug Delivery Reviews 55 315–328 (2003)

14. W Martanto et al, Mechanism of fluid infusion during microneedle insertion and retraction, J of Controlled Release 112 357–361 (2006)

15. JH Park, MG Allen and MR Prausnitz, Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery, J of Controlled Release 104 51–66 (2005)

16. CS Kolli and AK Benga, Characterization of solid maltose microneedles and their use for transdermal delivery, Pharm Research 25(1) 104–113 (Jan 2008)

17. FJ Verbaan et al, Assembled micro-needle arrays enhance the transport of compounds varying over a large range of molecular weight across human dermatomed skin, J of Controlled Release 117 238–245 (2007)

18. N Roxhead, P Griss and G Stemme, Membrane-sealed hollow microneedles and related administration schemes for transdermal drug delivery, Biomed Microdevices 10 271–279(2008)

19. Y Wang et al, Transdermal iontophoresis: Combination strategies to improve transdermal iontophoretic drug delivery, European J Pharm and Biopharm 60 179–191 (2005)

20. A Camirand and J Doucet, Needle Dermabrasion, Aesthetic Plast Surg. 21(1) 48–51 (Jan-Feb 1997)

21. G Micali et al, Mesotherapy for rejuvenation of photoaged skin: Ultrasound evaluation, J Am Acad Dermatol 58(2), supp. 2, AB23 (Feb 2008)

22. Derma Gold Roller Web site, available at: www.dermagoldroller.com (accessed Jun 23, 2008)

23. Environ Skin Care Pty, Ltd, Web site, www.environ.co.za (accessed Jun 23, 2008)

24. Clinical Resolution Laboratory Inc. Web site, www.microneedle.com (accessed Jun 23, 2008)

25. CosmeticSkinSolutions Web site, www.cosmeticskinsolutions.com (accessed Jun 23, 2008)

26. Vivida Skin Technology Web site, www.vivida.co.za (accessed Jun 23, 2008)

27. C Deutsch, Cosmetics Break the Skin Barrier, The New York Times (Jan 8, 2005), available at www.nytimes.com (accessed Sep 16, 2008) 

28. J Toon, Taking the ouch out of Needles: Arrays of micron-scale “microneedles” offer new technique for drug delivery, Georgia Tech Research News (Jun 2, 1998) 

29. Nanotechnology Task Force Report, US Food and Drug Administration (Jul 25, 2007), available at www.fda.gov (accessed Sep 17, 2008)

30. S Mahoney, Getting Under Your Skin, SpaFinder (May/June 2006), available at www.spafinder.com (accessed Sep 16, 2008)

31. L Benson, Skin Care Thinks Small to Deliver Big, GCI magazine (Aug 2008)

32. Skin Microactivation System and Method (US 2005/0203575 A1), US Patent Application Publication (Sep 15, 2005)                      




Microneedle Delivery Pros and Cons

 Microneedle Delivery Pros and Cons

Figure 1. Innovators

 Figure 1. Innovators

Figure 2. Microneedle

Figure 2. Microneedle 

Next image >