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Li, et al.
rapid drug delivery directly into the body without a time- The obtained solid microneedles do not have the stair-like
consuming slow penetration and release process, and surface and layer-by-layer structure that are associated
a higher drug utilization rate. By combining with the with the common 3D-printing technologies.
minimally invasive, painless, and convenient delivery Herein, we innovatively use the SOPL technique
of microneedles, HMNs have been used for transdermal for rapid customization of HMNPs within 5 s. In this
drug delivery of insulin [5,6] , vaccine [7,8] , lidocaine, etc. technology, the digital light is modulated by a digital
[9]
HMN patches (HMNPs) are commonly fabricated micromirror device (DMD) and projected to induce
using microelectromechanical systems (MEMS) spatial polymerization controlled by the distribution of the
techniques, including photolithography [10,11] , etching [12,13] , light intensity in the monomer solutions. After an annulus
laser direct writing, etc. In these methods, a thin picture is inputted into the DMD via the computer, the
[14]
substrate film is firstly created by chemical, physical vapor microneedles with hollow-cone structure can be precisely
deposition, or spin coating. Next, the two-dimensional printed in seconds. By adjusting printing pictures, various
master pattern of the required material is transferred structures of HMNs can be customized. The obtained
from the original photomask to the photosensitive film HMNs have smooth surfaces and good mechanical
on the substrate by photolithography technology. Finally, properties. After being equipped with a micro-syringe,
microneedles are made by wet or dry (plasma-based) the HMNP enables the quantitative, minimally invasive,
etching . However, MEMS techniques cannot achieve and pain-free insulin injection, which greatly reduces
[15]
the high-precision manufacturing of HMNs with fine physical pain and mental anguish.
structures. In addition, MEMS techniques can hardly be
used for customization and large-scale manufacturing 2. Materials and methods
because of the cumbersome, time-consuming, and costly 2.1. Materials
manufacturing processes. Therefore, the translation of
HMNPs to clinical applications is challenging and novel Photosensitive resin was purchased from Ausbond
techniques for rapid fabrication of HMNPs are urgently (China). Cell-Counting Kit-8 was purchased from
needed. SUNBAO BIOTECH (China). Quick-drying adhesive
Recently, three-dimensional (3D) printing was obtained from ergo (Switzerland). Agarose gel was
technology has been used to flexibly customize with purchased from Bioweste (Spain). Insulin injection was
intricate structures, and the manufacturing period has been purchased from Jiangsu Wanbang Biochemical Medicine
decreased to dozens of minutes [14,16-18] . For example, laser Co., Ltd (China). Streptozocin (STZ) was purchased
stereolithography (SLA) can be used to fabricate cone- and from BioFroxx (Germany). All chemical reagents were
pyramid-shaped HMNs and basic syringe-shaped needle of analytical grade. C57BL/6 mice were provided by
arrays (12.5 min are needed for the generation of each Chengdu Dossy Experimental Animals Co., LTD. Animal
device) . Liquid crystal display vat polymerization and studies were in compliance with the guidelines for the
[17]
digital light processing (DLP) have an improved molding ethical use of animals and were conducted at State Key
speed when constructing HMNs [16,19] . These 3D printing Laboratory of Biotherapy, Sichuan University, China.
technologies shorten the fabrication period and simplify 2.2. HMNPs customized by SOPL
the production processes of customized HMNs. However,
layer-by-layer additive manufacturing always resulted in a The main modules for SOPL equipment to prepare HMNPs
layered structure, which affects the mechanical properties are excitation light source, DMD chip, high magnification
of the microneedle and potentially causes needle break micromirror, and reservoir. Printing picture is one of the
and penetration failure during use. The layer-by-layer key points of this technology. The printing picture of a
structure can be improved by high printing precision, HMN, made of Adobe Photoshop CC 2019, consists of
such as high-precision two-photon polymerization (TPP). two non-concentric circles, which can be regarded as an
Moreover, TPP enables the fabrication of HMNs with annulus. Its small inner circle represents the unexposed
various straightforward shapes and small openings area, while the large outer circle represents the exposed
[20]
as well as in-plane and out-of-plane microneedles with area. Large circle and small circle are overlaid to form an
different aspect ratios [18,21] . However, it requires a long annular pattern of the exposure area. The size of the large
period to prepare microneedle arrays (10 min per needle) white circle represents the bottom size of the HMN. The
by TPP , leaving considerable room for improvement in size of the small black circle and the relative position to
[14]
terms of fabrication speed. Together, it remains a challenge the large circle represent the opening size and opening
to rapidly fabricate high-quality HMNs. Nonetheless, position of the HMN, respectively.
our group developed a 3D printing technology, namely The preparation of the HMN was as follows: First,
static optical projection lithography (SOPL), for rapid the printing picture of the HMN was inputted into a DLP
customizing high-quality solid microneedle arrays . LightCrafter 4500 Control Software. Second, a light beam
[22]
International Journal of Bioprinting (2022)–Volume 8, Issue 2 125