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Biological and Medical Applications of Materials and Interfaces

Additive Manufacturing of Honeybee-inspired Microneedle for Easy Skin Insertion and Difficult Removal Zhipeng Chen, Yinyan Lin, Weihsien Lee, Lei Ren, Bin Liu, Liang Liang, Zhi Wang, and Lelun Jiang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b09563 • Publication Date (Web): 09 Aug 2018 Downloaded from http://pubs.acs.org on August 10, 2018

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ACS Applied Materials & Interfaces

Additive Manufacturing of Honeybee-inspired Microneedle for Easy Skin Insertion and Difficult Removal Zhipeng Chen 1, Yinyan Lin 1, Weihsien Lee1, Lei Ren 1, Bin Liu 1, Liang Liang 2, Zhi Wang 2, Lelun Jiang *, 1 1. Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, School of Biomedical Engineering, Sun Yat-Sen University, Guangzhou 510006, PR China; 2. National Engineering Research Center of Near-net-shape Forming for Metallic Materials, South China University of Technology, Guangzhou 510640, PR China Tel: +86 20-39332153 Fax: +86 20-39332153 E-mail: [email protected] Abstract: With natural evolution, honeybee stinger with micro barbs can easily penetrate and trapped in the skin of hostile animals to inject venoum for self-defense. We proposed a novel 3D additive manufacturing method named magnetorheological drawing lithography (MRDL) to efficiently fabricate the bio-inspired microneedle imitating honeybee stinger. Under the assistance of external magnetic field, a parent microneedle was directly drawn on the pillar tip and tilted micro barbs were subsequently formed on the four sides of parent microneedle. Compared with barbless microneedle, the micro-structured barbs enable the bio-inspired microneedle easy skin insertion and difficult removal. The extraction-penetration force ratio of bio-inspired microneedle was triple of the barbless microneedle. The stress concentrations at the barbs helps to reduce the insertion force of bio-inspired microneedle by minimizing the frictional force while increase the adhesion force by interlocking barbs in the tissue during retraction. Such finds may provide an inspiration for the further design of barbed microtip-based microneedle for tissue adhesion, transdermal drug delivery, bio-signal recording, and so on. Keywords: Bio-inspired; Microneedle; magnetorheological drawing lithography; Penetration; Retraction; Finite element analysis 1. Introduction With hundreds of millions of years of evolution, many animals are equipped with different organs for accomplishing diverse physical acivities. Bio-microneedle can be found in some insects for the predation, defense and mating 1. Some bio-microneedles, such as fascicle of Aedes asbopictus mosquito 2-10, quill of North American porcupine

11

, caterpillar of Paras Consocia

12

, and stinger of worker honeybee

1, 13-15

, have been

evoluted with the backward-facing microstructured barbs on the surface, as shown in Table 1. These bio-microneedles with micro-structured barbs exhibit some ingenious physical proterties, such as painless insertion, low penetration force, high tissue adhesion, high stiffness and good biocompatibility mosiquito can painlessly pierce into skin and suck blood. Kong et al.

2, 4-6

12, 14, 16

. The

observed the proboscis of Aedes

albopictus mosquito and studied the insertion behavior of mosquito fascicle. The proboscis of mosquito was a jagged shaped bio-microneeedle. The mosquito fascicle can easily cut out skin under vibration at an average penetration force of 18 µN, which was three orders of magnitude smaller than the reported lowest penetration force for an artificial microneedle with an ultra shaprp tip to insert the human skin (10 mN) effortlessly pierce into skin and cause skin irritation. Ma et al.

12

17

. Caterpillar can

investigated the spine of Parasa Consocia

caterpillar. Many nanoscale backward barbs were regularly distributed on the spine surface. The caterpillar spine can penetrate mouse skin using a very small force (about 173 µN) without fracture and buckling failure. The researches of mosquito proboscis and caterpillar spine mainly focused on the insertion process but considered little on the pull process. North American porcupines use the quills in self-defense. Cho et al.

ACS Paragon Plus Environment

11

studied the

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penetration-retraction performance of the quills of North American porcupines. Each quill tip contained microscopic backward facing barbs. The micro-structured barbs on the quill can enable easy tissue penetration and difficult removal. The quill with barbs required 54 % less penetration force and 300 % more pull-out force compared with the barbless quill. But the quill of North American porcupine was in centimeter scale, larger than other bio-microneedles. Honeybee is well-known for its stinger to repel enemies and lay eaggs for reproduction. Our group

13-14

has investigated the mechanical behavior of worker honeybee stinger. Microbarbs can be

observed on the surface of stinger and the size becomes larger farther from the stinger tip. The honeybee stinger directly penetrated in the skin without vibration and was trapped in the skin with venom sac during the retraction, resulting in the death of honeybee. The average penetration force and pull-out force were 5.75 mN and 113.5 mN, respectively. The insertion force could be greatly minimized owing to the combination of ultrasharp stinger tip and micro barbs while the pull-out force could be seriously enhanced due to the mechanical interlocking of the barbs in the skin. Above all, micro-structured barbs on the surface of bio-microneedles can effectively lower the insertion force and significantly enhance the tissue adhesion. Table 1 Specific parameters of bio-microneedles Bio-microneedles

SEM images

Fascicle of Aedes asbopictus mosquito 2, 4-6

Spine of Paras Consocia caterpillar

12

Geometry

Penetration force

Length: 1.5-2.5 mm

Range: 6-38 µN

Diameter: 30 µm

Average: 18 µN

Length: 500-700 µm

Range: 80-265 µN

Diameter: 30-50 µm

Average: 173 µN

Quill of North

Length: several

American porcupine

centimeters

11

Diameter: 1.26 mm

Stinger of worker honeybee

13-14

Length: 1.8 mm Diameter: 90 µm

Pull-out force

NA

NA

Average:

Average:

0.043±0.013 N

0.44±0.06 N

Average: 5.75 mN

Average: 113.5 mN

Inspired by the natural bio-microneedle, scientists have already made great efforts to fabricate bio-mimicking microneedle. A lot of bio-inspired microneedles imitated mosquito’s proboscis were fabricated and verified

3, 7-10, 18-22

. The insertion force of bio-inspired microneedle can be significantly reduced using

viabration mode. The jagged shape of mosquito-inspired microneedle was usually fabricated by lithography and etching. But it requires complicated processes with expensive equipment located in a clean room. 3D laser lithographic also can be employed to fabricate hollow microneedle mimicking mosquito, but three-dimensional laser lithography system 'Nanoscribe GT' is extremely expensive 10. Cho et al.

11

also reproduced quills of North

American porcupine with nondeployable barbs using replica molding. This quill-inspired needle can significantly reduce penetration force and generate high tissue adhesion. Replica molding technique can easily copy


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bio-inspired needle in centimeter scale but it is very diffcutlt to fabricate sophisticated and complicated 3D bio-microneedle in micrometer scale. M. Sahlabadi and P. Hutapea

15

proposed 3D printing to manufacture

bioinspired needles by mimicking honeybee stinger for percutaneous procedure. The insertion force of the honeybee-inspired needles decreased by 21-35% in PVC gel insertion tests, and by 46 % in bovine liver tissue insertion tests. However, honeybee-inspired needles were also in the centimeter scale. In our previous study, our group

23

has proposed a novel magnetorheological drawing lithography (MRDL) method to efficiently fabricate

microneedle, bio-inspired microneedle and microneedle array molding-free. A bio-inspired microneedle with microstructured barbs imitated honeybee stinger was fabricated as a demo. But the fabrication process and the penetration-retraction performance of honeybee-inspired microneedle has not been investigated and discussed yet. Based on our previous researches on the mechanical behavior of honeybee stinger, we proposed the MRDL as an additive manufacturing method to fabricate 3D honeybee-inspired microneedle with microstructured barbs over the surface. The MRDL method is simple and low cost

23

. It can produce extremely complex

microstructures, which are very difficult to accomplish with traditional subtractive manufacturing or lithography technology. The fabrication mechanism and process of bio-inspired microneedle will be discussed. The morphology of bio-inspired microneedle will be characterized. The penetration-retraction performance of bio-inspired microneedle will be experimentally investigated compared with barbless microneedle. The pentration-rectraction mechanism will be further analyzed by finite element analysis (FEA) using cohesive zone model 24, which is firstly applied in skin penetration and removal for bio-inspired microneedle to our knowledge.

2. Experimental Section 2.1 Materials preparation A curable magneto-rheological fluid (CMRF) was prepared for the formation of bio-inspired microneedle using MRDL technique. Iron particles (average diameter of 1 µm, Naiou Nano Technology Co., Ltd, China) were purchased as the magnetic particles, and epoxy novolac resin (Weiyi Metallography Experiment Instrument Co., LTD, China) was used as the curable carrier. The magnetic particles were uniformly dispersed into the curable carrier at a mass ratio of 3: 4. The mixture was subsequently pre-polymerized to adjust its viscosity at a temperature of 80 °C for 150 s to fabricate parent microneedle and 200 s to fabricate of micro barbs, respectively. Fresh rabbit skin was prepared for the ex-vivo skin penetration-retraction tests. A New Zealand rabbit (male, 3 months old, and 3.0 kg) was purchased from Xinhua Experimental Animal Farm (Huadu District, Guangzhou, China). The rabbit was humanely euthanized by intravenous injection of pentobarbital. The hair was removed and the skin was cut into squares with the sizes of 50 × 50 mm2 and a thickness of 2.5 ± 0.1 mm. All animal procedures conducted in this work were reviewed, approved, and supervised by the Institutional Animal Care and Use Committee (IACUC) at the Sun Yat-sen University (Approval Number: IACUC–DD–16–0904).

2.2 Fabrication of bio-inspired microneedle A custom-made setup was also developed for the fabrication of bio-inspired microneedle, as shown in Fig. S1. The information was descripted in the supporting information. The fabrication process of bio-inspired microneedle using MRDL technique can be divided into two steps: (1) fabrication of parent microneedle, and (2) fabrication of micro barbs on the curved surface of parent microneedle, as shown in Fig. S2. CMRF properties can be influenced by the operation temperature and the whole bio-inspired microneedle was fabricated at a room



temperature of 25 ℃.

(1) Fabrication of parent microneedle The fabrication process of parent microneedle under a uniform magnetic field is shown in Fig. S2(a). The intensity of external magnetic field was approximately 80 mT generated by a cylindrical NdFeB permanent magnet (size: ϕ 30×4 mm, N40, JIUCI, China). A drawing pillar (tip diameter: ϕ 700 µm, copper) was driven by the linear motor toward a pool filled with CMRF. The drawing pillar was inserted into the CMRF, stopped for 1 s, and moved back at a speed of 1.5 mm·s-1. A liquid microneedle was formed on the pillar tip. This fabrication process was digitally controlled using a custom-made software based on Visual Basic. The formation process of liquid microneedle was recorded by an optical microscope. The liquid microneedle was maintained under the external magnetic field and pre-baked by hot air blowing at a temperature of 80 °C for 15 min. The pre-baked microneedle was further solidified in an oven at a temperature of 100 °C for 1 h. The parent microneedle was fabricated. The formation process of parent microneedle were simulated by FEA software COMSOL Mutiphysics (V5.3, COMSOL Inc., Sweden). The magnetic field distribution of three typical states during the formation process were calculated. Their geometric models were reconstructed by Solidworks (V2016 SP0, Dassault Systems, France) based on the captured images of three typical states. The images of three typical states are shown in Figure 2. The models were meshed with tetrahedral, and the element size was set as “extremely fine”, as shown in Fig. S3. The relative permeability of CMRF, permanent magnets, drawing pillar and air were set 2.15, 1.05, 1 and 1, respectively. The external magnetic field intensity was 80 mT. The equivalent magnetic charge method was employed to calculate the magnetic field distribution.

(2) Fabrication of micro barbs The fabrication process of micro barbs on the curved surface of parent microneedle is shown in Fig. S2 (b). It can be divided into three main stages: drawing, angle transferring, and solidifying of liquid micro barbs. The magnetic field distribution used for the fabrication of micro barbs was numerically calculated as shown in Fig. S1 (b). The fabricated parent microneedle was horizontally fixed at the drawing region of magnetic field. The drawing pillar (tip diameter: ϕ 250 µm, solidified CMRF) handed with a CMRF droplet was moved towards and slightly compressed on the surface of parent microneedle. Subsequently, the drawing pillar was moved back at a speed of 1.5 mm/s, forming a liquid micro barb on the surface of parent microneedle under an external magnetic field. Above formation procedures were repeated, and the liquid micro barbs in a line were fabricated. The angle of these liquid micro barbs was turned along the direction of the external magnetic field as the parent microneedle was translated from the “drawing region” to “angle transferring region”. The liquid micro barbs were pre-solidified by hot air blowing at a temperature of 80 °C for 10 min. The parent microneedle was rotated 90°. Another pre-solidified micro barbs in a line were fabricated by repeating above process. Finally, micro barbs on the four sides of parent microneedle were fabricated. The whole fabrication process was digitally controlled using a custom-made software and monitored by an optical microscope. The pre-solidified bio-inspired microneedle was further baked in an oven at a temperature of 100 °C for 1 hour. The solidified bio-inspired microneedle was observed using an SEM (JSM-6380LA, JEOL, Japan). The drawing and angle transferring of liquid micro barbs were also numerically calculated by COMSOL Mutiphysics. The geometric models were reconstructed by Solidworks based on the captured images of the typical states, as shown in Figure 3. The models were meshed with tetrahedral, and the element size was set


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“extremely fine”, as shown in Fig. S4. The relative permeability of CMRF, drawing pillar, parent microneedle, and air were also set 2.15, 2.15, 2.15 and 1, respectively. The intensities of external magnetic field for drawing and angle transferring were approximately 90 mT and 270 mT, respectively. The equivalent magnetic charge method was used to calculate the magnetic field distribution. 2.3 Skin penetration-retraction test of bio-inspired microneedle (1) Penetration-retraction test A mechanical loading equipment was custom-made for the skin penetration-retraction test of bio-inspired microneedle, as shown in Fig. S5. Under a relative humidity of 80 %, a fresh rabbit skin was pinned on a polystyrene foam, which was used to mimic the soft tissue under the skin 14, 25. The bio-inspired microneedle was bonded on the probe of force sensor. The bio-inspired microneedle driven by the linear motor was moved towards the rabbit skin, inserted into skin with a loading displacement of 1.5 mm at a speed of 10 µm/s, stayed still for 2 min, and subsequently pulled back at a velocity of 10 µm/s until the bio-inspired microneedle was completely removed from the skin. The loading force and displacement were recorded synchronously. The whole process of penetration-retraction test was recorded by the microscope. A barbless microneedle (parent microneedle without barbs) was repeated above test following the same experimental procedures. (2) Numerical simulation In order to further understand the penetration-retraction mechanism, the stress distribution in the skin was numerically calculated using FEA software COMSOL Multiphysics for a simplified bio-inspired microneedle with two-pair barbs. This study focused on the effect of micro barbs on skin penetration and removal, so a 2D plane-strain model under dynamical condition was built for simplicity. The finite element models of bio-inspired microneedle and barbless microneedle are shown in Figure 1(a) and Figure 1(b), respectively.

Figure 1 The finite element models for penetration-retraction of (a) bio-inspired microneedle, and (b) barbless microneedle in skin. The skin is a nonlinear viscoelastic material and the mechanical properties are complicated. A simplified viscoelasticity model of skin was proposed according to the previous report 26. The size of skin model was 5×2.5 mm2. The thickness of stratum corneum layer was 35 µm. Kelvin-Voigt material model of skin was introduced and the relaxation time was set 180 s based on the experimental result of penetration-retraction test. The specific parameters of skin are listed in Table 2. Cohesive zone model was utilized in crack propagation analysis 24. The cohesive zone was defined by cohesive contact pairs along the ideal vertical cracking path in the middle of the skin, as shown in Figure 1. A bilinear traction-separation law for cohesive zone was used to implement damage ଵ

in the finite element mesh 24. Coresspondingly, the energy release rate was calculated by ‫ ܩ‬ൌ ଶ ߪߜ. δ was equal to the diameter of the microneedle tip, and σ was the strength of the cohesive zone. σ was set to the failure stress of skin layers. The mesh of skin was defined by mapped and the mesh size was set extra fine.



Page 6 of 24

Table 2 The mechanical parameters of human skin for simulation

Parameters

Stratum corneum 3

27

Dermis 1200 26

Density (kg/m )

1300

Failure stress (MPa)

20 28

7 26

Friction coefficient

0.42 29

0.42 29

Young's modulus (kPa)

34 30

3400 31

Possion's ratio

0.48 30

0.48 30

Thickness (µm)

35

2500

The model geometry of bio-inspired microneedle with two-pair backward barbs was built that approximated the fabricated one as closely as possible. The tip width of parent microneedle was 20 µm. The barb tip width was 5 µm. The barbs on the parent microneedle were stretching out with an angle of approxiametly 40°. The space between the adjacent barbs was 200 µm. The mesh of bio-inspired microneedle was defined by mapped and the size was set standard. The whole bio-inspired microneedle was set as prescribed velocity. The bio-inspired microneedle was inserted into the skin in the vertical direction at a speed of 10 µm/s. The insertion depth was 800 µm. The bio-inspired microneedle was hold still for 180 s, and subsequently retracted from the skin at a velocity of 10 µm/s. All contact in the model was defined using penalty. Contact along the predetermined crack path between bio-inspired microneedle and skin was modeled with frictional coefficient of 0.42. Fixed constraint was applied on the left, right and bottom boundary. The Von-Mises stress distribution of skin and reaction force on the bio-inspired microneedle were numerically calculated using solid mechanics module of COMSOL. The FEA of penetration-retraction of barbless microneedle (parent microneedle without barbs) was also performed by following the similar procedures. 3. Results and discussion 3.1 Fabrication of bio-inspired microneedle A 3D bio-inspired microneedle imitating a honeybee stinger was fabricated by MRDL technique mold-free, as shown in Video S1. It was an additive manufacturing process, which could be divided into two main steps: the fabrication of parent microneedle on the pillar tip, and the subsequent formation of micro barbs on the curved surface of parent microneedle. (1) Fabrication of parent microneedle The formation process of liquid parent microneedle on the pillar tip can be divided into three typical states: contacting, self-thinning and break-up. The images and magnetic field distributions of three typical states are shown in Figure 2. As the pillar is longitudinally moved downwards and inserted into the CMRF pool. The pillar tip is immersed and wrapped by CMRF, as shown in Figure 2(a). As the pillar is moved upwards, the wrapped CMRF is drawn from the pool, and forms a liquid bridge between the CMRF pool and pillar tip. The liquid bridge is elongated with extensional drawing, resulting in an elasto-capillary self-thinning 32, as shown in Figure 2(b). The liquid bridge is in a dynamical steady-state to maintain this extensional deformation without rupture 33. It is mainly governed by the vertical balance of drawing force, magnetic force, surface tension, gravity and viscous force

23

. The magnetic intensity in the liquid bridge increases as the bridge gets thinner, as shown in

Figure 2(b). The magnetic particles are magnetized by the external magnetic field, inducing a gradient magnetic


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field in the bridge, which increase the magnetic force. The drawing force, surface tension and gravity try to pinch off the liquid bridge while the magnetic force and viscous force try to prevent it. Therefore, a significant axial necking driven by the surface tension owing to the Gibbis-Marangoni effect occurs at the mid-liquid bridge. This dynamical necking induces a local extensional stress at the central region of liquid bridge. As the drawing is further proceeded, the local stress gradually increases and reaches the rupture limit of the waist-shaped liquid bridge, triggering an instability and resulting in a sudden break-up. It is similar to that observed in the breakup of a plastic material. This liquid bridge is split into two daughter parts: one left on the pool and the other maintained on the pillar tip. Once the liquid bridge is divided in two parts, an extremely sharp liquid microneedle is formed on the pillar tip under the external magnetic field, as shown in Figure 2(c). However, the liquid microneedle on the pillar tip is in a Rosensweig instability 34. Without application of strong external magnetic field, this sharp microneedle tip will be self-shrunk and becomes blunt due to high surface tension at tip. This is a dynamical self-assembling process. The magnetic field in the liquid microneedle on the pillar tip was numerically calculated and its distribution is shown in Figure. 2(c). The intensity of magnetic field in liquid microneedle is great, especially at the microneedle tip. The magnetic particles in liquid microneedle is magnetized and attracted each other, forming the chains and nets in the carrier

35-36

. The chains and nets served as a structural support in the carrier stop the

further self-shrinking of microneedle tip. Once the vertical combination effect of magnetic force, gravity and surface tension on the microneedle tip reaches a new balance, the self-assembling process of the liquid microneedle is completed, and its shape can be maintained under the external magnetic field. The self-assembled liquid microneedle on the pillar tip is heated and solidified owing to polymerization reaction of epoxy resin. Finally, a parent microneedle is fabricated on the pillar tip.

Figure 2 The formation process of parent microneedle on the pillar tip and its magnetic field distriubtions simulated by COMSOL: (a) contacting, (b) self-shrinking, and (c) break-up (2) Fabrication of micro barbs The fabrication of micro barbs on the 3D curved surface of parent microneedle consists of two key stages: drawing and angle transferring of liquid micro barbs, as shown in Figure 3(a). A magnetic field perpendicular to the parent microneedle is applied. A pillar tip hanged with a CMRF droplet is compressed and spread on the surface of parent microneedle. The compressed CMRF droplet is subsequently stretched to be a liquid bridge by withdrawing the pillar. The liquid bridge gets thinner, forms a neck at the central region, gradually promotes the onset of an instability, and finally results in a breakup. This process is similar to that observed in the formation of liquid microneedle on the pillar tip. The magnetic field distribution in the liquid bridge is also similar, as shown



Page 8 of 24

in Figure 3(a) and Figure 2. A liquid micro barb with an extremely sharp tip is left on the surface of parent microneedle. The barb tip will be self-shrunk under the external magnetic field. The equilibrium shape of micro barb can be obtained as the net energy of this system is minimized

36

. The change in potential energy on micro

barb is the sum of the gravitational, surface tension, and magnetic potential energies

34

. The gravitational and

surface tension potential energies decrease while the magnetic potential energy concomitantly increases with the self-shrinking of barb tip. As the net energy of the system is minimized, the micro barb is finally self-assembled and formed on the curved surface of parent microneedle. The magnetic field distribution of the parent microneedle at the cross section was numerically calculated, as shown in Figure 3(b). The gradient of magnetic field determines the magnetic force. The magnetic field intensity at point “r” is higher than the magnetic field intensities at the point “s” and “q”. Therefore, the magnetic force prevents the CMRF of liquid barb droping from the upper surface of parent microneedle under the effect of gravity. The micro barbs in a line along the parent microneedle can be repeatedly fabricated by following above procedures. These liquid micro barbs straightly stand on the upper surface of parent microneedle along the magnetic field direction. As the direction of external magnetic field is changed, the angle of liquid micro barbs is transferred, and the tilted micro barbs is formed on the parent microneedle, as shown in Figure 3(a). A great gradient of magnetic field in the barb is produced by change of the magnetic field direction, which induces a magnetic force and torque. The liquid micro barb is subjected to magnetic force and torque, resulting in a rotation of micro barb. The potential magnetic energy of a liquid micro barb is minimum along the external magnetic field direction, as shown in Figure 3(c). Therefore, the angle of liquid barb is turned and barb tip is pointed along the magnetic field direction. In a word, the tilt angle of the liquid microneedle/barb is mainly determined by the direction of external magnetic field. In principle, we can fabricate tilted micro barbs with any angle by changing direction of external magnetic field. The tilted micro barbs in a line are solidified. A bio-inspired microneedle can be finally fabricated as the tilted micro barbs are formed and solidified on the four sides of the parent microneedle. The fabrication of bio-inspired microneedle using the MRDL technique is a 3D additive manufacturing process. This process demonstrates MRDL is a simple technique that can fabricate extremely complex microstructures, which are very difficult to accomplish with traditional subtractive manufacturing or lithography technology 23.


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Figure 3 (a) The fabrication process of micro barbs on the parent microneedle and its magnetic field distributions calculated by COMSOL, (b) the magnetic field distribution surround the cross section of parent microneedle, and (c) the magnetic energy of a micro barb under different magnetic field directions. 3.2 Characterization of bio-inspired microneedle A parent microneedle without barbs is shown in Figure 4(a). It inherits the equilibrium shape of liquid parent microneedle drawn by MRDL technique. The shape looks like a cone. The length, diameter at the middle section, and tip radius of parent microneedle are approximately 2000 µm, 200 µm and 10 µm, respectively. After making statistics and analysis, the mean apex angle of parent microneedle was approximately 14° under the external magnetic field intensity of 80 mT for a given drawing speed and prepared CMRF. The morphology of bio-inspired microneedle is shown in Figure 4(b-c). 5 micro barbs in a line are orderly distributed along the parent microneedle, and total 20 micro barbs are symmetrically on the four sides of parent microneedle. The barbs have dimensions ranging from 35 µm to 50 µm in length, with a maximum tip radius of 2.5 µm. The size of micro barbs becomes larger farther from the tip of parent microneedle, which was adjusted by the volume of CMRF droplet hanged on the tip of drawing pillar 23. There is approximately 200 µm space between the adjacent barbs. The tilted barbs on parent microneedle are stretching out with an average angle of approximately 40°. The surface of bio-inspired microneedle is rough, which distributes a lot of magnetic microparticles. Furthermore, the chains formed from the agglomeration of magnetic particles can be observed on the surface of bio-inspired microneedle. These chains distribute along the direction of external magnetic field applied. It indirectly suggests the existence of chains in the carrier, which likely support the equilibrium shape of the liquid microneedle or micro barb from self-shrinking and collapsing. The barbs and parent microneedle of bio-inspired microneedle are



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fabricated in the micro scale and millimeter scale, respectively. It indicates that MRDL is a flexible technique that can easily fabricate multi-scale microneedles.

Figure 4 The SEM images of: (a) the parent microneedle, (b) the bio-inspired microneedle, and (c) the barbs on the parent microneedle. 3.3 Mechanics performance (1) Penetration-retraction performance To

explore

the

skin

penetration-retraction

performance

of

bio-inspired

microneedle,

the

penetration-retraction tests were performed in comparison with the barbless microneedle, as shown in Video S2. The test results of bio-inspired microneedle and barbless microneedle are showed in Figure 5. The penetration-retraction process can be divided into three stages: insertion, relaxation, and retraction. The force required for penetration into skin was defined as the penetration force, and the maximum force required to remove the microneedle with respect to baseline was defined as the pull-out force 11, 13.

Figure 5 (a) The penetration-retraction performance of bio-inspired microneedle in comparison with barbless microneedle. The penetration-retraction processes of (b) bio-inspired microneedle, and (c) barbless microneedle. During the insertion stage, the skin initially deforms once the bio-inspired microneedle tip gets in contact with its top surface. The insertion force increases till a critical load leads to the skin penetration. A sudden drop of force at the peak point “Q1” can be observed, which is the critical penetration force of bio-inspired microneedle into top layer of skin, according to the previous report 14, 37. The penetration force and work are 41.7 mN and 20.8 µJ, respectively. At this critical load, the compressing tip induces an extremely high stress on the contact point of the skin, and initials a planar mode I crack ahead of tip, permitting the skin penetration 11. Once the bio-inspired microneedle penetrates into the skin, the insertion force continuously increases with loading displacement. In this quasi-static insertion stage, the bio-inspired microneedle needs to deform and slice through the skin tissue and to overcome the incremental friction force. The insertion force and work of bio-inspired microneedle at the loading displacement of 1.5 mm are 124.9 mN and 48 µJ, respectively. In comparison with bio-inspired microneedle, the barbless microneedle exhibits a similar profile of insertion plot. The penetration


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force and work of barbless microneedle are 50.8 mN and 19.8 µJ, respectively. The penetration force and work required for bio-inspired microneedle and barbless microneedle are very close owing to their similar sharpness of tips

16, 38

. However, the insertion force for barbless microneedle increases more rapidly after skin penetration

compared with bio-inspired microneedle. The total insertion force and work required for barbless microneedle at the loading displacement of 1.5 mm are 200.7 mN and 60 µJ, respectively. Compared with bio-inspired microneedle, the insertion force and work of barbless microneedle increase 1.6 times and 1.25 times, respectively. The backward barbs could separate parent microneedle with tissue, changing surface contact to point contact so that it could reduce the resistance of friction during the insertion stage

14, 39

. Therefore, the bio-inspired

microneedle is easier for skin insertion. The effect of barbs on insertion will be further discussed using FEA. During the relaxation stage, the bio-inspired microneedle holds still for 2 mins. The residual force decreases from 124.9 mN to 55.5 mN, and reaches a steady state. The residual insertion energy on the skin is gradually relaxed with time because the skin is a viscoelastic material. The residual force of barbless microneedle shows a sharper decline due to the larger skin deformation during the insertion stage. During the retraction stage, the bio-inspired microneedle is pulled back from the skin, and the resistance force rapidly turns from compression state to tensile state. The skin is gradually stretched to be an up concaved profile by bio-inspired microneedle. The pull-out force and work of bio-inspired microneedle are 73 mN and 35 µJ, respectively. Compared with bio-inspired microneedle, it is easier to remove the barbless microneedle from the skin. Its pull-out force and work are only 28 mN and 8 µJ, respectively. The extraction-penetration force ratio can be used to quantify the difficulty for microneedle extracting from the skin compared with penetrating 39. The extraction-penetration force ratio is 1.75 for bio-inspired microneedle and 0.55 for barbless microneedle. The micro barbs of bio-inspired microneedle are anchored in skin tissue as it is pulled back. The micro barbs may be deployed and bent during removal from skin. The deployment of micro barbs increases the tissue adhesion by projecting barbs radially away from the parent microneedle to increase resistance of friction and promote mechanical interlocking with tissue

14, 23

. As the removal further proceeds, some interlocked tissues are teared

from the skin and adhere on the surface of bio-inspired microneedle, as shown in Figure 5(b4). The barbs on the bio-inspired microneedle are still kept intact after penetration and removal. It indirectly indicates the bio-inspired microneedle has good mechanical strength. However, the surface of barbless microneedle is clear, as shown in Figure 5(c4). It suggests that the skin tissue is damaged less during penetration and removal of barbless microneedle. Above all, the bio-inspired microneedle is much more difficult removal from skin in comparison with barbless microneedle. (2) FEA According to above discussion, the insertion force can be considerably decreased and the pull-out force can be dramatically enhanced owing to the existence of micro barbs. To visualize the effect of barbs on the penetration- retraction, we calculated the stress distribution in skin using FEA for bio-inspired microneedle and barbless microneedle, as shown in Video S3 and Figure 6(a). During the insertion of bio-inspired microneedle, the stress concentrations occur not only at tip area of parent microneedle but also at the tip areas of barbs compared with barbless microneedle. The local stress concentrations generated by the barbs are likely to separate the direct contact between parent microneedle and tissue to reduce the frictional force surrounding bio-inspired microneedle to decrease the insertion force. Therefore, the bio-inspired microneedle requires less insertion force and work to pierce into tissue compared with barbless microneedle. During the relaxation stage, the stress



gradually decreases with time, which indicates the residual energy absorbed from the insertion stage is gradually released. During the retraction of bio-inspired microneedle, the extremely high stress of skin concentrates at the tip areas of barbs. This stress may reach the rupture limit of skin tissue, and then barb tips are anchored in the skin. The barbs are interlocked with the skin as the bio-inspired microneedle is pulled back compared with barbless microneedle, as shown in Figure 6(b). The interaction between the barbs and tissue is responsible for high mechanical adhesion of bio-inspired microneedle. The reaction force versus loading displacement plot of bio-inspired microneedle and barbless microneedle during the penetration-retraction process was numerically calculated by COMSOL, as shown in Figure 6(c). It presents the similar profiles compared with that obtained by the penetration-retraction experiments shown in Figure 5(a). It indirectly verifies the correction of numerical analysis. However, the pull-out force for barbless microneedle is zero by calculation while 28 mN by experiment. There existed the adhesion force between barbless microneedle and skin tissue in experiment, which was ignored in the numerical analysis. Furthermore, the surface of barbless microneedle filled with magnetic microparticles is rough owing to existence of magnetic particles on the surface of parent microneedle, which can increase the frictional force between barbless microneedle and tissue during the retraction stage.

Figure 6 (a) The stress distributions in the skin during the penetration-retraction process of bio-inspired microneedle and barbless microneedle, (b) the overlay pictures of fitted skin pulled by bio-inspired microneedle and barbless microneedle at the unloading displacement of 780 µm, and (c) the calculated penetration-retraction performance of bio-inspired microneedle in comparison with barbless microneedle.


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4. Conclusions We proposed the MRDL technique fabricate honeybee-inspired microneedle with micro barbs. It was an additive manufacturing process that parent microneedle was firstly drawn on the pillar tip, and micro barbs were subsequently formed on the curved surface of parent microneedle under the assistance of external magnetic field. Tilted micro barbs symmetrically distributed on the four sides of parent microneedle and became larger farther from the tip of bio-inspired microneedle. The bio-inspired microneedle required less insertion force and work to pierce into tissue while needed larger pull-out force and work to remove in comparison with barbless microneedle. The extraction-penetration force ratio was 1.75 for bio-inspired microneedle and 0.55 for barbless microneedle. The local stress concentrations generated by the barbs were likely to separate the direct contact between parent microneedle and tissue to reduce the frictional force, facilitating easy insertion. The barbs were anchored in the skin during the retraction, which significantly enhanced the pull-out force. We hope the findings can serve as the basis for the development of bio-inspired devices, such as tissue adhesives 40, tissue cutting 41, or barbed microneedles for transdermal drug delivery 42-43, micro-scale biopsy 44, and bio-potential monitoring 45. Associated Content The Supporting Information is available. MRDL setup (Fig. S1), The illustration of fabrication process of bio-inspired microneedle (Fig. S2), FEA models of three typical states of parent microneedle fabrication (Fig. S3), FEA models during the fabrication of micro barbs (Fig. S4), Mechanical loading equipment (Fig. S5). (PDF) The fabrication process of honeybee-inspired microneedle. (AVI) The penetration-retraction test of bio-inspired microneedle into rabbit skin in comparison with barbless microneedle. (AVI) The FEA results of the penetration-retraction process of bio-inspired microneedle in comparison with barbless microneedle. (AVI) Acknowledgements This research is financially supported by the National Natural Science Foundation of China (Project No. 51575543), the Science and Technology Planning Project of Guangdong Province, China (Project No. 2017A030303009) and the Pearl River Nova Program of Guangzhou, China (Project No. 201806010194). Conflicts of Interest The authors declare no conflict of interest. References (1) Wu, J.; Yan, S.; Zhao, J.; Ye, Y. Barbs Facilitate the Helical Penetration of Honeybee (Apis mellifera ligustica) Stingers. Plos One 2014, 9 (8), e103823. (2) Kong, X. Q.; Wu, C. W. Measurement and Prediction of Insertion Force for the Mosquito Fascicle Penetrating into Human Skin. Journal of Bionic Engineering 2009, 6 (2), 143-152. (3) Ramasubramanian, M. K.; Barham, O. M.; Swaminathan, V. Mechanics of a Mosquito Bite with Applications to



Microneedle Design. Bioinspiration & Biomimetics 2008, 3 (4), 046001. (4) Kong, X.; Wu, C. Numerical Simulation of Mosquito Fascicle Inserting into Human Skin. Mechanics in Engineering 2010, 32 (2), 90-94,99. (5) Kong, X. Q.; Wu, C. W. Mosquito proboscis: An Elegant Biomicroelectromechanical System. Phys Rev E 2010, 82 (1), 011910. (6) Kong, X.; Qu, Y.; Zhang, W.; Wu, C. Insertion Force of Mosquito Fascicle Penetrating into Human Skin. Science & Technology Review 2013, 31 (22), 60-63. (7) Jaiswal, S.; Muthuswamy, S. Instability Analysis of Mosquito Fascicle under Compressive Load with Vibrations and Microneedle Design. J Bionic Eng 2015, 12 (3), 443-452. (8) Lenau, T. A.; Hesselberg, T.; Drakidis, A.; Silva, P.; Gomes, S. Mosquito inspired medical needles. Bioinspiration, Biomimetics, and Bioreplication 2017, 10162 (08), 1-13. (9) Shoffstall, A. J.; Srinivasan, S.; Willis, M.; Stiller, A. M.; Ecker, M.; Voit, W. E.; Pancrazio, J. J.; Capadona, J. R. A Mosquito Inspired Strategy to Implant Microprobes into the Brain. Sci Rep-Uk 2018, 8, 1-10. (10) Suzuki, M.; Takahashi, T.; Aoyagi, S. 3D Laser Lithographic Fabrication of Hollow Microneedle Mimicking Mosquitos and its Characterisation. International Journal of Nanotechnology 2018, 15 (1-3), 157-173. (11) Cho, W. K.; Ankrum, J. A.; Guo, D.; Chester, S. A.; Yang, S. Y.; Kashyap, A.; Campbell, G. A.; Wood, R. J.; Rijal, R. K.; Karnik, R.; Langer, R.; Karp, J. M. Microstructured Barbs on the North American Porcupine Quill Enable Easy Tissue Penetration and Difficult Removal. P Natl Acad Sci USA 2012, 109 (52), 21289-21294. (12) Ma, G. J.; Shi, L. T.; Wu, C. W. Biomechanical Property of a Natural Microneedle: The Caterpillar Spine. J Med Devices 2011, 5 (3), 1-6. (13) Ling, J.; Jiang, L.; Chen, K.; Pan, C.; Li, Y.; Yuan, W.; Liang, L. Insertion and Pull Behavior of Worker Honeybee Stinger. J Bionic Eng 2016, 13 (2), 303-311. (14) Ling, J.; Song, Z.; Wang, J.; Chen, K.; Li, J.; Xu, S.; Ren, L.; Chen, Z.; Jin, D.; Jiang, L. Effect of Honeybee Stinger and its Microstructured Barbs on Insertion and Pull Force. J Mech Behav Biomed 2017, 68, 173-179. (15) Sahlabadi, M.; Hutapea, P. Novel Design of Honeybee-Inspired Needles for Percutaneous Procedure. Bioinspiration & biomimetics 2018, 13 (3), 036013-036013. (16) Ma, G.; Wu, C. Microneedle, Bio-microneedle and Bio-inspired Microneedle: A review. J Control Release 2017, 251, 11-23. (17) Roxhed, N.; Gasser, T. C.; Griss, P.; Holzapfel, G. A.; Stemme, G. Penetration-enhanced Ultrasharp Microneedles and Prediction on Skin Interaction for Efficient Transdermal Drug Delivery. J Microelectromech S 2007, 16 (6),


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The TOC Graphics


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The finite element models for penetration-retraction of (a) bio-inspired microneedle, and (b) barbless microneedle in skin.



The formation process of parent microneedle on the pillar tip and its magnetic field distriubtions simulated by COMSOL: (a) contacting, (b) self-shrinking, and (c) break-up


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(a) The fabrication process of micro barbs on the parent microneedle and its magnetic field distributions calculated by COMSOL, (b) the magnetic field distribution surround the cross section of parent microneedle, and (c) the magnetic energy of a micro barb under different magnetic field directions.



The SEM images of: (a) the parent microneedle, (b) the bio-inspired microneedle, and (c) the barbs on the parent microneedle.


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(a) The penetration-retraction performance of bio-inspired microneedle in comparison with barbless microneedle. The penetration-retraction processes of (b) bio-inspired microneedle, and (c) barbless microneedle.



(a) The stress distributions in the skin during the penetration-retraction process of bio-inspired microneedle and barbless microneedle, (b) the overlay pictures of fitted skin pulled by bio-inspired microneedle and barbless microneedle at the unloading displacement of 780 µm, and (c) the calculated penetration-retraction performance of bio-inspired microneedle in comparison with barbless microneedle.


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Additive Manufacturing of Honeybee-Inspired ... - ACS Publications

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