**7. Conclusions**

type and source of the materials (e.g., human and animal origin) are critical to the regulatory approval process. A product composed of two or more regulated components, that is, drug/ device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity is defined as a combination product [90]. The FDA (Food and Drug Administration, United States) regulation of a combination product (e.g., delivery system for wound healing) is mainly determined by the component with the primary mode of action. According to the classification of the product, the clinical trials (for premarket approval, PMA) must provide valid scientific evidence of safety and efficacy to support the indicated use of the wound healing delivery systems. Generally, preclinical studies contain toxicity studies and animal model evaluations. Delivery systems of drugs, bioactive proteins, cells, and genes in wound healing and nanomedicine should test their biocompatibility according to ISO 10993, including dermal irritation, dermal sensitization, cytotoxicity, acute systemic toxicity, hemocompatibility/hemolysis, pyrogenicity, mutagenicity studies, subchronic toxicity, chronic toxicity, and immunogenic potential [91]. Good clinical practices (GCPs) are the standards for designing, conducting, recording, and

For example, autologous stem cells are under clinical trial and are effective in ulcer healing and angiogenesis. However, translating delivery of stem cell application in *in vitro* and *in vivo* experiments from animal models to human clinical trials is still in its infancy. Preclinical studies suggest that cell delivery systems represent an effective and safe therapeutic strategy in the treatment of nonhealing wounds. More clinical studies on human subjects, including better data management of the patients and long‐term follow‐up of the patients' conditions, are necessary. Improved stem cell delivery vehicles in large‐scale human clinical trials may be promising for diabetics with foot ulcers. There are no serious complications or side effects, but its therapeutic mechanisms, effects, and standardization still require further research [92]. While delivery system‐based products offer increasingly important strategies for managing complex wounds, potential drawbacks include the risks of infectious agent transfer and immunological rejection. The manufacturing process, transport, and storage of delivery systems in wound healing are major cost implications; thus, their current clinical use remains limited [93]. Many current clinical trials are placing a high emphasis on addressing safety issues in all stem cell therapies, including stem cell delivery in wound healing [94]. The serious adverse effects of stem cell delivery are mainly immune response and tumorigenic potential. Delivery systems used in cell therapy encompass four main approaches, which are systemic administration, injection, topical, and local deliveries. Localized delivery of cells in wound healing is an optimal delivery approach for wound treatments [95]. Nonimmunogenic, nontoxic, biodegradable, and biocompatible biomaterials have been developed as carriers of stem cells that can protect cells and improve wound healing. However, clinical use of stem cells, for example, allogeneic EPCs, is currently inhibited by the risk of immunogenicity and tumorigenicity. To modulate the immune response, mesenchymal stromal cells or umbilical cord blood is already used in clinical trials, but definitive results are still pending. MSCs are known to be hypoimmunogenic [96]. Current challenges are standardized and quality‐ controlled cell therapy, the differentiation of MSCs to unwanted tissue, and potential tumori‐ genicity [94]. MSCs have been applied clinically for the treatment of diabetic wounds. Long

reporting clinical trials required for Class III medical devices.

86 Wound Healing - New insights into Ancient Challenges

In the past few decades, many wound dressings and skin substitutes have been developed to treat skin loss and wounds. Delivery systems have been proven to improve wound healing and skin tissue regeneration. Polymeric microspheres and nanospheres, nanoparticles, nanofibrous structures, hydrogels, and scaffolds have been developed to deliver drugs to wound sites, overcoming the challenges caused by antibiotic‐resistant microbial infections. Controlled release of drug delivery systems has been of increasing interest, as well as the applications of nanotechnology and biomaterial scaffolds. Growth factor and peptide delivery systems applied in skin wound healing help in the regeneration of tissue, reduction of scarring, and reconstruction of blood capillaries (neovascularization). Keratinocytes, fibroblasts, endothelial cells, mesenchymal stem cells, adipose‐derived stem cells, and endothelial progenitor cells studied in delivery systems have great promise in chronic wounds and diabetic ulcers. Gene therapies now in clinical trials and the discovery of biodegradable polymers, fibrin meshes, and human collagen serving as potential delivery systems may soon be available to clinical wound management. However, regeneration of peripheral nerves is seldom reported. Looking toward the future, these delivery wound healing products may be able to achieve the replacement and regeneration of more normal skin; to gain localized delivery to wound site; to heal severe burns, chronic and complex wounds; to control the release of drugs, growth factors, and cells; and to silence genes.
