Review Article
Advances in drug delivery systems (DDSs) to release growth factors for wound healing and skin regeneration

https://doi.org/10.1016/j.nano.2015.03.002Get rights and content

Highlights

  • Chronic wounds affect about 1-2% of the European and United States population, which results in a significant economic burden estimated to be nearly 2-4% of the health budgets mainly associated with hospitalisation, nursing time (the two most expensive costs), frequent dressing changes and related bacterial infections.

  • Current therapies are far from guarantying adequate healing and recurrence is frequent.

  • There is a critical need to develop new treatment alternatives able to reduce the healing time, confer protection against proteases, promote oxygen permeability and stimulate endogenous cytokines and GF delivery.

  • New developments for wound management have focused not only on finding new medicines for wound healing, but also on improving the effectiveness of current existing therapies.

  • Current advances on DDSs used for the controlled release of GFs are based on polymeric micro and nanospheres, lipid nanoparticles, nanofibrous structures, hydrogels and scaffolds

  • Advanced DDSs improve treatment safety, by reducing the dose and treatment frequency, and optimise therapy effectiveness, by prolonging the GF effect.

  • Combination of different DDSs for tissue engineering are the most promising approach as these type of systems can act as double DDSs for GF delivery, mimicking the GF delivery observed physiologically.

  • In the near future these delivery systems will provide efficient formulations for the treatment of chronic wounds and skin regeneration.

Abstract

Current advances in novel drug delivery systems (DDSs) to release growth factors (GFs) represent a great opportunity to develop new therapies or enhance the effectiveness of available medical treatments. These advances are particularly relevant to the field of regenerative medicine, challenging healthcare issues such as wound healing and skin repair. To this end, biocompatible biomaterials have been extensively studied to improve in vivo integration of DDSs, to enhance the bioactivity of the released drugs and to deliver bioactive molecules in a localised and controlled manner. Thus, this review presents an overview of DDSs to release GFs for skin regeneration, particularly emphasising on (i) polymeric micro and nanospheres, (ii) lipid nanoparticles, (iii) nanofibrous structures, (iv) hydrogels and (v) scaffolds. In addition, this review summarises the current animal models available for studying wound healing and the clinical trials and marketed medications based on GF administration indicated for chronic wound treatment.

From the Clinical Editor

Chronic wounds currently pose a significant burden worldwide. With advances in science, novel drug delivery systems have been developed for growth factors delivery. In this comprehensive review, the authors highlighted current drug delivery systems for the enhancement of wound healing and their use in clinical settings.

Graphical abstract

This review summarises the latest drug delivery systems to release Growth factors developed for healing enhancement, the animal models commonly used for the study of wound healing and the clinical trials and current marketed medications based on growth factors (Graphical abstract: Figure 1).

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Introduction

Over the past years, the prevalence of people suffering from chronic wounds has dramatically increased. Many factors including age, smoking, obesity and chronic diseases, such as diabetes, venous and arterial insufficiency, can delay wound healing and increase the risk of developing chronic wounds.1 Chronic wounds affect about 1-2% of the European and United States (US) population, which results in a significant economic burden estimated to be nearly 2–4% of the health budgets.1, 2 In Europe, wound management implies an average cost per patient and year of 6.000€–10.000€,3 associated with hospitalisation, nursing time (the two most expensive costs), frequent dressing changes and related bacterial infections. Wound care costs the US healthcare system $50 billion annually, including an average cost to heal per wound between $3.349–9.358.4 Moreover, current therapies are far from guarantying adequate healing and recurrence is frequent; thus, health care resources are ineffectively used, alarmingly increasing the total health care expenditure worldwide. Therefore, improvement of chronic wound treatments has become a major need; hence, the scientific community has focused not only on finding new treatments for wound healing, but also on improving the effectiveness of current therapies, such as the administration of growth factors (GFs) for wound repair. In this regard, significant efforts have been made to develop new drug delivery systems (DDSs) to release active compounds in a controlled manner.

This review provides a general overview of the current advances on DDSs used for the controlled release of GFs for chronic wound treatment, particularly focusing on, polymeric micro and nanospheres, lipid nanoparticles, nanofibrous structures, hydrogels and scaffolds. In addition, this review summarises the current animal models available for wound healing studies and the clinical trials and marketed medications based on GF administration indicated for chronic wound care.

Section snippets

Chronic wounds and cutaneous wound healing

Cutaneous wound healing is a complex physiological event designed not only to restore the skin barrier function and homeostasis, but also to reduce the risk of infection and further complications. Chronic wounds are those that have failed to restore the anatomical and functional integrity of the skin over a period of three months.5 Such wounds, unlike acute wounds, remain in a pathological inflammatory stage.6 As a consequence, proinflamatory cells and cytokines recluted at the lesion promote a

Animal models for wound healing studies

Wound repair is a well-coordinated biological process that involves the integrated interaction of different growth factors, cytokines, enzymes and cell types, such as inflammatory cells, keratinocytes, fibroblasts and endothelial cells.14, 15 Our understanding of the physiologic wound process has increased over the past decades mainly due to the use of a wide range of animal models, as the study of wound healing in patients is limited by obvious ethical considerations. The use of animal models

Growth factors: a promising approach to wound healing

Growth factors are biologically active polypeptides which are involved in cell growth, differentiation, proliferation, migration and metabolism.48 GF effects are a consequence of the specific binding to their receptors which activates a cascade of molecular events. All stages of the healing process are controlled by a wide variety of GFs and cytokines. This review sums up the major GFs involved in wound healing and skin repair, particularly focusing on: epidermal growth factor (EGF), platelet

Clinical trials and marketed medications

The administration of GFs for chronic wound treatment has been used for several decades. Therefore, there are a number of medications available on the market based on this therapeutic approach. GFs are usually administered in solution or using classical formulations, such as creams, gels or ointments. The clinical trials performed to assess the safety, tolerability and efficacy of GF administration are summarised in Table 2.

As can be seen in Table 2, Regranex® (Becaplermin), a gel approved by

Novel DDSs to release growth factors

This section summarises the different DDSs developed to date to provide controlled release of GFs for the treatment of chronic wounds, mainly focusing on polymeric micro and nanospheres, lipid nanoparticles, nanofibrous structures, hydrogels, scaffolds and their combinations, as shown in Figure 1. In addition, at the end of this section, Table 3 provides a summary of the novel DDSs developed for wound healing enhancement.

Conclusions

Chronic wounds are a serious health issue that is dramatically growing around the world. Current therapies usually involve the use of different types of dressings principally focused on improving life quality of patients and reducing pain. External administration of GFs to promote healing has proven to be effective in wound care; however, its use is been associated to stability problems due to the proteases present at the wound site. Thus, there is a critical need to develop new treatment

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    Conflict of interest: No potential conflicts of interest were disclosed.

    Declaration of Interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.

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