Multifunctional Silk Fibroin Methacryloyl Microneedle for Diabetic Wound Healing

Abstract

of diabetes mellitus. Globally, these wounds are important causes of disability and mortality. [2] Diabetic wounds that fail to heal are largely caused by oxidative stress. [3] Overproduction of reactive oxygen species (ROS) and inadequate antioxidant protection results in excess oxidative stress, leading to cell apoptosis and suppressed cell proliferation as well as differentiation at diabetic wound sites. [4] In high glucose (HG) conditions, glucotoxicity disrupts angiogenesis, thereby limiting the transport and delivery of nutrients and oxygen in diabetic wounds. [5] Diabetic skin wounds are more susceptible to bacterial infections, causing belated healing and life-threatening outcomes. [6,7] Bacterial infections are also involved in oxidative stress induction. [8] Excess oxidative stress levels suppress growth factor-mediated signaling pathways, resulting in dysregulated angiogenesis. Oxidative stress, angiogenesis, and bacterial infections have been reported to jointly cause diabetic wound healing disorders. [9] The existing therapies include drugs or application of bio-activators, hyperbaric oxygen therapy, and stem cell therapy. [10][11][12] However, these therapies are expensive, single-functional, immature, and cumbersome to operate in many cases. [13,14] The limited efficacies create an urgent need for the development of novel treatment modalities.Microneedle (MN) patches are emerging minimally-invasive local delivery systems that have the ability to overcome the dosing inefficiency of systemic delivery. And the new-generation MN, such as bioinspired or stimuli-responsive MN, exhibits more individualized, more efficient, and more convenient. [15,16] These patches have been applied for the treatment of various diseases, including skin wounds. [17,18] However, the current MN patches cannot act on multiple targets of diabetes wound pathogenesis. [19] We developed a multifunctional MN patch with the ability to simultaneously target oxidative stress, angiogenesis, and bacterial infections in diabetic wounds. A silk fibroin methacryloyl hydrogel was selected as the base material for multifunctional MN patches. Silk fibroin methacryloyl was formed from silk fibroin, a physiologically inactive protein derived from Bombyx mori silkworm cocoon, modified with glycidyl-methacrylate groups to supply a cross-linkage site essential for photopolymerization. Silk fibroin methacryloyl has excellent biocompatibility, biodegradability, stable mechanical Diabetic wound is one of the common complications in diabetic patients, which exhibits chronic, hard-to-heal characteristics. The healing process of wounds is impaired by several factors, including excessive oxidative stress, blocked angiogenesis, and bacterial infection. The therapeutic effects of traditional microneedle patches remain not satisfactory, due to their difficulty simultaneously targeting multiple targets to treat diabetic wounds. As such, there is an urgent need to develop a multifunctional microneedle (MN) patch for promoting the healing of diabetic wounds. ...

Extracellular vesicle-loaded hydrogels for tissue repair and regeneration

“…5 B). One method for overcoming this limitation involves the use of microneedles (MNs) [ 178 ]. The materials commonly used in the preparation of MNs include gelatin, PLGA, PVA, and chitosan.…”

Functional acellular matrix for tissue repair

“…Under these conditions, autografting remains the standard of care [ 246 , 247 ] but is not suitable for large burns because of the limited availability of skin grafts and is less effective for treating diabetic wounds [ 248 ]. Diabetic wounds are one of the most common diabetic complications, and they are chronic and difficult to heal [ 249 ]. Growth factors are essential for regulating the cellular response to the wound healing process [ 250 , 251 ].…”

Microneedles for in situ tissue regeneration

“…B) Schematic presentation of MN-PBNs-VEGF for diabetic wound healing (Reproduced with permission of Ref. [ 93 ]). …”

“…The base of MNs could release polymyxin to inhibit bacterial infection. Due to the interconnected porous structure of hydrogel MNs, PBN and VEGF could be slowly released into the wound tissue after the MNs swelling [ 93 ]. The use of the base, which plays a mechanically supportive role, as a drug carrier allows the preparation of multifunctionally integrated MNs and can, to a certain extent, solve the problem of low loading of dissolving and hydrogel MNs.…”

“… [ 92 ] Silk fibroin methacryloyl Arrays: 385 needles Height: 700 ​μm Shape: conical Strength:- Prussian blue nanozymes, VEGF, polymyxin Polymyxin in the base inhibited bacterial infections; Nanozymes and VEGF loaded needles facilitated diabetic wound healing. [ 93 ] PVA Arrays: 10 ​× ​10 Height: 750 ​μm Shape: pyramidal Strength:- α-amylase, levofloxacin-loaded polydopamine nanoparticles The needle tip penetrated the biofilm; Under NIR irradiation, amylase was released to expose bacteria in the biofilm and combine the photothermal effect and antibiotics to kill the bacteria. [ 107 ] Chitosan Arrays: 20 ​× ​20 Height: 600 ​μm Shape: conical Strength:- VEGF VEGF loaded temperature responsive hydrogel in needles released drugs induced by the inflammation response at the site of wounds.…”