Nanotechnology-Based Medical Devices for the Treatment of Chronic Skin Lesions: From Research to the Clinic

Abstract

Chronic wounds, such as pressure ulcers, diabetic ulcers, venous ulcers and arterial insufficiency ulcers, are lesions that fail to proceed through the normal healing process within a period of 12 weeks. The treatment of skin chronic wounds still represents a great challenge. Wound medical devices (MDs) range from conventional and advanced dressings, up to skin grafts, but none of these are generally recognized as a gold standard. Based on recent developments, this paper reviews nanotechnology-based medical devices intended as skin substitutes. In particular, nanofibrous scaffolds are promising platforms for wound healing, especially due to their similarity to the extracellular matrix (ECM) and their capability to promote cell adhesion and proliferation, and to restore skin integrity, when grafted into the wound site. Nanotechnology-based scaffolds are emphasized here. The discussion will be focused on the definition of critical quality attributes (chemical and physical characterization, stability, particle size, surface properties, release of nanoparticles from MDs, sterility and apyrogenicity), the preclinical evaluation (biocompatibility testing, alternative in vitro tests for irritation and sensitization, wound healing test and animal wound models), the clinical evaluation and the CE (European Conformity) marking of nanotechnology-based MDs.

Keywords: CE marking; biocompatibility; chronic wounds; clinical evaluation; critical quality attributes; medical devices; nanotechnologies; wound models.

Figure 1

(a) Centrifugal spinning, (b) direct drawing technique and (c) electrospinning apparatus. Modified from [61] with permission.

Figure 2

Images of nanofibrous scaffolds as dermal substitutes: (a) polymer-based matrix; (b) polymer-based matrix embedded with silver nanoparticles; (c) polymer-based matrix embedded with halloysite and (d) with montmorillonite adapted from [53,54,55]. CC BY 4.0.

Figure 3

Concept of Quality by Design (QbD) for the development of medical devices (MDs) and the different steps with the corresponding technology readiness level (TRL). Modified from [74]. CC BY 4.0.

Figure 4

From the idea to the market of a MD. Modified from [77]. CC BY 4.0.

Figure 5

CLSM (confocal laser scanning microscope) images of a cell substrate (normal human dermal fibroblasts) with a free cell area (lesion) obtained using an insert (panel (A)) and the same substrate 24 h after the insert removal characterized by cells migrated/proliferated in the free area (panel (B)) (the cell substrate has been stained with phalloidin-FITC (green, F-actin filaments) and DAPI (blue, nucleus)). Scale bar 100 μm. Modified from [135]. CC BY 4.0.

Figure 6

Different stages of the clinical evaluation. Modified from [195]. CC BY 4.0.

Figure 7

Design control documentation, evidence, and results in the life cycle for medical devices. Modified from [201] with permission.