Degradable microneedle patches loaded with antibacterial gelatin nanoparticles to treat staphylococcal infection-induced chronic wounds
Graphical abstract
Introduction
Chronic wounds, including diabetic foot ulcers, pressure ulcers, tumor wounds, and surgical damages, seriously endanger people's physical and mental health and impose a heavy burden on the socioeconomic system [1], [2]. Bacterial infection, which is usually accompanied by the formation of biofilms, often interferes with the normal wound healing cascades and has been recognized as the major cause of chronic wounds [3], [4]. Biofilms are collections of bacteria that attach to the surface of injured tissue. They are found to have strong resistance to the body's innate immune system and are insensitive to antibiotic treatment, due to the dense barriers that limit the penetration of antibacterial agents [5], [6]. Studies have shown that biofilms are presented in >90 % of chronic wounds and can induce excessive inflammation, result in the prolonged release of inflammatory cytokines, and lead to repeated infections and non-healing of skin wounds [7], [8].
Microneedle (MN) patches loaded with antibacterial drugs are recognized as one of the most effective ways to combat chronic wounds on the skin [9], [10]. MNs with appropriate lengths can penetrate the epidermis to create channels in the skin while avoiding contact with capillaries and nerves, featuring a minimally invasive and painless delivery strategy to reach the biofilm formed underneath the skin [11], [12]. Researchers have developed a variety of MNs that consist of antibacterial materials such as chitosan [13], [14], antibacterial silver nanoparticles [15], antimicrobial peptides (AMP) [16], [17], and bioactive extracts [18], [19]. For example, MNs containing the antimicrobial agent chloramphenicol have been developed and used to treat bacterial biofilms. MNs can penetrate biofilms and promote the release of chloramphenicol in response to the bacterial community, which significantly reduces the off-target toxicity of the drug [20]. Thus, MNs loaded with active regenerative agents and antibacterial drugs hold promise to combat infection-induced chronic wounds, such as diabetic foot ulcers.
On another note, photothermal therapy as a new antibacterial approach is gaining increasing attention in the scientific community [21], [22], [23]. Based on the photothermal conversion of the chemical agents, light energy is transformed into heat to kill bacteria at the infection site [24], [25]. Moreover, nanoparticle-based drug delivery systems are showing great promise in the diagnosis and treatment of various diseases [26], [27], [28], [29], and several systems are currently in clinical use [30], [31]. Nanoparticles have several advantages over conventional formulations, such as high drug loading capacity, protection against enzyme/chemical degradation, controlled drug release, storage stability, etc. [32], [33], [34]. Among these carriers, gelatin nanoparticles (GNPs) are highly degradable in the body, and the rich surface functional groups allow the installation of targeting motifs or create a responsive release to ambient stimuli (pH, enzymes, or temperature) [35], [36], [37].
In this work, we report a degradable MN patch made of a physically inert polymer PVP K-30 and a recombinant Type III collagen protein to deliver antibacterial GNPs to the dermis of infected chronic wounds. The GNPs are conjugated with an antibacterial photothermal peptide AMP-Cypate and the peptide will be released in the presence of gelatinase overexpressed by Staphylococcus aureus (S. aureus). The MN-mediated physical delivery combined with the chemoenzymatic responsive release has shown outstanding therapeutic efficacy for chronic wound healing in diabetic mice.
Section snippets
Materials
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), Fmoc-protected amino acids, Rink Amide-MBHA resin and N-hydroxybenzotriazole (HOBt) were obtained from GL Biochemical Ltd. (Shanghai, China). Recombinant human collagen III (Col III) was purchased from Jiangsu Trautec Medical Technology Co., Ltd. (collagen content >90 %, batch number: 20180823), N-(3-(dimethylamino)-propyl-N′-ethylcarbodiimide) hydrochloride (EDC), phosphate-buffered saline (PBS buffer),
Nanoparticle preparation and characterization
A two-step desolvation method has been used to prepare GNPs [39], [40], [43]. To get monodispersed GNPs with reduced aggregation and enhanced stability, the low molecular weight gelatin fraction in the supernatant was discarded during the first step and the high molecular weight gelatin fraction was re-dissolved to form GNPs in the second desolvation step. Fig. 1a shows that the obtained AMP-Cypate@GNP particles are close to spherical in shape with a size of ~200 nm under TEM. SEM image of
Conclusions
We have successfully prepared a smart antibacterial patch with degradable MNs and enzyme-responsive release of an antibacterial photothermal peptide. The MN/AMP-Cypate@GNP patch features several articulate designs. First, MNs are moisture sensitive and biodegradable due to the PVP and Col III. The MNs dissolve within 20 min in the skin, which readily releases the cargo loaded in the tip. This ensures a rapid and complete release of the antibacterial agents at the infection site in the dermis.
CRediT authorship contribution statement
Xiaoling Lei, Mengjin Li: Conceptualization, Validation, Investigation, Formal analysis, Investigation, Visualization, Writing - original draft.
Cheng Wang: Methodology, Writing - original draft, Funding acquisition.
Pengfei Cui, Lin Qiu, Shuwen Zhou, Pengju Jiang: Project administration, Supervision, Resources, Writing - review & editing.
Haihang Li, Donghui Zhao: Resources, Writing - review & editing.
Xinye Ni, Jianhao Wang, Jiang Xia: Conceptualization, Funding acquisition, Supervision, Writing
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgment
We acknowledge funding support from the QingLan Project of Jiangsu Province, the Natural Science Foundation of Jiangsu Province (BK20221381), the Science & Technology Support Program of Changzhou (Socy Development CE20225047) the International Scientific Cooperation Project of Changzhou Scientific Bureau (grant number CZ20200015) and Science & Technology Support Program of Changzhou (Application Basic Research, No. CJ20210142). This research was also supported by a company grant (ref.
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These authors contributed equally to this work.