**9. Recent work in chronic wound healing using microneedles**

In the case of chronic wounds, the delivery of topically administered therapeutics is disrupted due to the discharge of exudate, the presence of eschar, and a harsh

#### **Figure 20.**

*A flow chart to represent the various applications of microneedles in the medical field including drug delivery, vaccine and gene delivery, ocular drug delivery, combination therapy, and biomacromolecule delivery [33].*

chemical microenvironment rich in various enzymes. Therefore, to make therapeutics more available at the wound bed and also control the distribution of the drug spatially, by having control over the drug content of individual needles, MNA systems are developed. Based on the control temporal release profile, MNAs are classified as passive, active, and smart releases [34]. Researchers have utilized these different strategies to deliver different therapeutics to enhance the healing of the wound process and solve the crucial dysfunctions existing in the chronic wound microenvironments [35].

### **9.1 Passively delivered biological materials**

This method is one of the simplest available methods to carry biologics from MNAs, despite the fact that alteration of release kinetics is not possible when the passive release MNA is in action. However, they can be altered during the development phase of MNAs by changing various components of the system design. Several chronic wound symptoms, such as low vascularization and infection, are addressed using this technique [36]. Fabrication of MNA using an antibiotic agent encapsulated within an MNA structure or an antibacterial material is the straightforward approach to creating antibacterial MNA. Both the concepts mentioned above were achieved by Yi et al. by filling zinc nitrate (Zn2+) into chitosan (CS) MNs, which defeated unloaded CS MNs in the eradication of *S. aureus* and *E. coli*. The worth of piercing the biofilm to eliminate infection was highlighted when the MNAs were capable enough to kill a large number of bacteria compared to a topically applied film with the same

*Minimally Invasive Microneedle: A Novel Approach for Drug Delivery System and Infected… DOI: http://dx.doi.org/10.5772/intechopen.105771*

#### **Figure 21.**

*(A) The different parts of hybrid microneedle including the scaffolding material used for preserving the stem-cell functionality offered by the core-shell structure for facile insertion, (B) the mechanism involved in MNA-based delivery of stem cell action meant for enhanced regeneration [38].*

composition [37]. The different parts of the hybrid microneedle including the scaffolding material used for preserving the stem-cell functionality offered by the coreshell structure for facile insertion are shown in **Figure 21A**. **Figure 21B** shows the mechanism involved in MNA-based delivery of stem cell action meant for enhanced regeneration.

#### **9.2 Active system**

MNAs that work on passive delivery of biological materials provide effortless and smoothly applicable point of care (POC) systems. It does not adhere to the needs connected with the wound environment, which is dynamic in nature throughout the process of healing. The effect of therapeutics is different at different stages of wound healing. Therapeutics that may improve healing at one stage of healing can prove to be harmful or useless at a different stage. The application of active MNA systems could be a promising alternative to passive MNAs. In this mechanism, the dissolving Gantrez® AN-139 MNA was loaded with photosensitizing methylene blue to perform photodynamic antimicrobial chemotherapy (PACT). In this approach, the photosensitizing drug is activated using light, which releases reactive radicals. The targeted bacteria are broken down by these reactive radicals [39]. The 3D printed SEM image of hollow microneedles is shown in **Figure 22A**. **Figure 22B** shows the smartphonecontrolled wireless pumping system that is able to deliver therapeutics on demand.

#### **9.3 MNAs based on smart systems/stimuli-responsive**

An additional mechanism in the engineering of systems based on MNA for better healing of the wound is by using smart materials. These smart materials can respond to changes in the environment of the wound. Smart systems are the combination of responsiveness of active systems, which can react to the dynamic requirements of the chronic wound and user simplicity of passive release MNAs. In a recent study of this strategy, the fabrication of MNAs is from a combination of VEGF-loaded NIPAM hydrogel and antibacterial chitosan. NIPAM is temperature sensitive. The release of VEGF from the permeable hydrogel network is triggered by an increase in the temperature of a chronic inflamed wound. The lack of vascularization and bacterial infection are addressed by combining chitosan with VEGF loading. The capability of MNA to kill most of the bacteria in both E. coli and S. aureus cultures was shown in

#### **Figure 22.**

*(A) The MNA integrated with flexible microfluidic patch for drug distribution in the wound bed. Figure shows a 3D printed SEM image hollow microneedles. (B) The smartphone controlled wireless pumping system which is able to deliver the therapeutics on demand [39].*

#### **Figure 23.**

*(A) The mechanism involved in release of VEGF into the wound bed with the increase in temperature during wound inflammation. (B) The mechanism involved in MNA patch action. (C) Fabricated-MNA (top) MNA which is loaded with fluorescent-labelled drugs (bottom) [40].*

the antibacterial test. The MNA patch developed was applied to the rats with severely infected wounds, in which it was found that the VEGF-loaded MNA group showed the thickest granulation tissue and the most wound closure. It also demonstrated increased deposition of collagen, angiogenesis, and downregulated inflammatory response.

The MNA systems are also fabricated using bacteria-responsive smart materials to treat infected wounds [40].

**Figure 23A** shows the mechanism involved in the release of VEGF in the wound bed with the increase in temperature during wound inflammation.

The mechanism involved in the MNA patch is shown in **Figure 23B**. **Figure 23C** shows the fabricated MNA on the top and MNA loaded with florescent loaded drugs in the bottom.

### **9.4 Mechanically interacting systems**

The wound closures are improved by using MNAs and by the physical application of mechanical forces. The MNAs developed are to bring about mechanical interlocking after insertion due to swelling. The mechanism of interlocking by using MNAs helps

*Minimally Invasive Microneedle: A Novel Approach for Drug Delivery System and Infected… DOI: http://dx.doi.org/10.5772/intechopen.105771*

the process of healing a wound by inducing wound closure and protecting the tissue from mechanical stress. This is achieved using hybrid core-shell structured MNAs consisting of a non-swellable core and a swellable hydrogel shell. After insertion, the ISF is absorbed by the hydrogel, due to which physical entanglement is induced through the swelling of microneedle tips. There has been a significant increase in the resistance against bacterial incursion compared to surgical staples using MNA patches. The application of MNA patches has also limited the scar formation and tissue damage. The use of MNA patches also enhances the mechanical strength of tissues that are healed, which consequently reduces the susceptibility of wound reopening. The mechanism also improves both external and internal wound closure rates compared to suture application in rats. Mechanically self-interlocking needles can hold the MNA in place for a long-term drug delivery which makes them appealing. This strategy can replace the use of sutures on wounds [41].

#### **9.5 Bioinspired design for efficient drug/vaccine coating**

Biomimetics is an interdisciplinary scientific field that is aimed to solve complex technological issues. It focuses on the imitation and study of biological systems. The lateral sides of pyramidal MNs are ornamented, with European true bugs structure, facilitating an efficient and directional liquid transport. Two-photon polymerization (TPP) is used to realize this kind of MNs. To prove that these MNs pierce the skin, both *ex vivo* skin tests and *in vivo* tests were performed. The arrays of MNs can be replicated accurately using a micro-molding technique. **Figure 24** shows an image depicting the idea behind biomimetics [42].

#### **9.6 Photon-based smart bandage**

Wound healing can be assessed by measuring the pH of the wound. This method is one of the most potential wound healing assessment methods. It indicates the condition and the stage of wound healing. Photons-based smart bandages for assessing wound healing present the first smart wound dressing for pH assessment. This method is based on embedded optical fiber. Optical fibers are pH sensitive and are embedded in gauze fabric and hydrocolloid wound dressing. A fiber-embedded bandage can measure pressure as low as 0.1 kPa and has high linearity in the range of 0–0.3 kPa. This is due to the low Young's modulus of PDMS, which is the component

of the system. The smart bandage, based on optical fiber, is capable of assessment of pressure and pH in the wound region simultaneously [42].
