Drug delivery systems and materials for wound healing applications

doi:10.1016/j.addr.2018.04.008

Review

. 2018 Mar 1:127:138-166.

doi: 10.1016/j.addr.2018.04.008. Epub 2018 Apr 5.

Drug delivery systems and materials for wound healing applications

Affiliations

¹ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Materials Design Division, Faculty of Materials Science and Engineering, Warsaw University of Technology, Warsaw 02-507, Poland.
³ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIRA Institute of Biomedical Technology and Technical Medicine, Department of Developmental BioEngineering, University of Twente, Enschede, The Netherlands.
⁴ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The University of Chicago Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
⁵ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran.
⁶ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, United Kingdom.
⁷ Division of Plastic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁸ Department of Mechanical and Materials Engineering, University of Nebraska, Lincoln, NE 68508, USA.
⁹ Materials Design Division, Faculty of Materials Science and Engineering, Warsaw University of Technology, Warsaw 02-507, Poland.
¹⁰ Center of Nanotechnology, King Abdulaziz University, Jeddah 21569, Saudi Arabia.
¹¹ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical and Materials Engineering, University of Nebraska, Lincoln, NE 68508, USA. Electronic address: atamayol@unl.edu.
¹² Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center of Nanotechnology, King Abdulaziz University, Jeddah 21569, Saudi Arabia; Department of Chemical and Biomolecular Engineering, California NanoSystems Institute (CNSI), University of California, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, CA 90095, USA; Department of Radiology, University of California, Los Angeles, CA 90095, USA; Department of Physics, King Abdulaziz University, Jeddah 21569, Saudi Arabia. Electronic address: khademh@ucla.edu.

PMID: 29626550
PMCID: PMC6003879
DOI: 10.1016/j.addr.2018.04.008

Review

Drug delivery systems and materials for wound healing applications

Saghi Saghazadeh et al. Adv Drug Deliv Rev. 2018.

. 2018 Mar 1:127:138-166.

doi: 10.1016/j.addr.2018.04.008. Epub 2018 Apr 5.

Authors

Affiliations

¹ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Materials Design Division, Faculty of Materials Science and Engineering, Warsaw University of Technology, Warsaw 02-507, Poland.
³ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIRA Institute of Biomedical Technology and Technical Medicine, Department of Developmental BioEngineering, University of Twente, Enschede, The Netherlands.
⁴ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The University of Chicago Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
⁵ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran.
⁶ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, United Kingdom.
⁷ Division of Plastic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁸ Department of Mechanical and Materials Engineering, University of Nebraska, Lincoln, NE 68508, USA.
⁹ Materials Design Division, Faculty of Materials Science and Engineering, Warsaw University of Technology, Warsaw 02-507, Poland.
¹⁰ Center of Nanotechnology, King Abdulaziz University, Jeddah 21569, Saudi Arabia.
¹¹ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical and Materials Engineering, University of Nebraska, Lincoln, NE 68508, USA. Electronic address: atamayol@unl.edu.
¹² Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center of Nanotechnology, King Abdulaziz University, Jeddah 21569, Saudi Arabia; Department of Chemical and Biomolecular Engineering, California NanoSystems Institute (CNSI), University of California, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, CA 90095, USA; Department of Radiology, University of California, Los Angeles, CA 90095, USA; Department of Physics, King Abdulaziz University, Jeddah 21569, Saudi Arabia. Electronic address: khademh@ucla.edu.

PMID: 29626550
PMCID: PMC6003879
DOI: 10.1016/j.addr.2018.04.008

Abstract

Chronic, non-healing wounds place a significant burden on patients and healthcare systems, resulting in impaired mobility, limb amputation, or even death. Chronic wounds result from a disruption in the highly orchestrated cascade of events involved in wound closure. Significant advances in our understanding of the pathophysiology of chronic wounds have resulted in the development of drugs designed to target different aspects of the impaired processes. However, the hostility of the wound environment rich in degradative enzymes and its elevated pH, combined with differences in the time scales of different physiological processes involved in tissue regeneration require the use of effective drug delivery systems. In this review, we will first discuss the pathophysiology of chronic wounds and then the materials used for engineering drug delivery systems. Different passive and active drug delivery systems used in wound care will be reviewed. In addition, the architecture of the delivery platform and its ability to modulate drug delivery are discussed. Emerging technologies and the opportunities for engineering more effective wound care devices are also highlighted.

Keywords: Drug delivery; Microtechnologies; Nanotechnologies; Transdermal delivery; Wound healing.

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Figures

**Figure 1**
Schematic representation of four stages of wound healing and their time scale. Figure is reproduced with permission from references [11].

**Figure 2**
Materials for wound dressings. (a,b) Fabrication of ZnO incorporated chitosan dressing. (c) SEM images showing the microstructure and the ZnO nanoparticles. (d) The effectiveness of the chitosan-based dressings with commercial dressings (Kaltostat) and negative control, confirming the superiority of the engineered dressings. (e) SEM image of Kaltostat commercially available dressing. (f,g) Two different alginate-based dressings fabricated by EDC-activated crosslinking of alginate with polyethylene imine (f) and ethylenediamine (g). Figures are reproduced with permission from references [76] and [80].

**Figure 3**
Electrospun scaffolds for the treatment of chronic wounds. (a) The microstructure of electrospun GelMA scaffolds before and after 24 h incubation in PBS. (b, c) The effect of incorporation of GelMA nanofibers and gelatin constructs on the flap necrosis and vascularization. (d) Images of implanted electrospun nanofibrous membranes and the adjacent skin flap. Parts d-f is showing the color laser Doppler detection of skin flaps perfusion (7 days post surgery), confirming the better therapeutic outcome of GelMA nanofiber. (e) Schematic demonstration of the EGF loading into nanofibrous scaffolds. Images showing the effectiveness of inducing wound healing in the diabetic animal receiving nanofibrous scaffolds loaded with EGF. Figures are reproduced with permission from references [97], [104].

**Figure 4**
(a) Schematic showing the use of GelMA hydrogel for epidermal regeneration. (b) The comparison of the stratified epidermis formation on both collagen and GelMA-based scaffolds, showing the comparable effectiveness of GelMA hydrogels. (c) The fabrication of composite nanofibers of ZnO and PCL. The incorporation of branched microparticles resulted in the formation of rose-mimicking structures with nano features. (d) The effect of nanospikes on enhancing the adhesion strength of the rose-mimicking nanofibrous scaffolds to surrounding tissues. (e) The better effectiveness of composite rose-mimicking scaffolds in inhibiting bacterial growth. (f) The larger pores in the composite scaffolds facilitated keratinocytes penetration. Figures are reproduced with permission from references [115] and [119].

**Figure 5**
Techniques for fabrication of drug delivery tools. (a) The process of fabricating PLGA-based drug carriers through double emulsion process. (b, c) Micrographs of the fabricated particles containing CHX and PDGF-BB. (d) The effect of dual drug delivery on wound healing rate. (e) Droplet-based microfluidic platform for fabrication of porous microgels. (f) Fabrication of multi-compartment drug carriers using microfluidic systems. Figures are reproduced with permission from references [190], [194], and [193].

**Figure 6**
Microneedle arrays as transdermal drug delivery tools in skin care. (a) Schematic showing different types of microneedles used for transdermal drug delivery. (b) Bi-layer microneedles with dissolvable tips carrying insulin before and after implantation. (c,d) Microneedles with swellable tips used for better adhesion of skin flaps to the surrounding tissues. (e,f) Swellable microneedles used as self-locking drug delivery tools. Figures are reproduced with permission from references [207], [204], [211], and [212].

**Figure 7**
Intracellular delivery tools. (a) Schematic of the gold nanoparticle decorated with nucleic acids (SNA). (b) The downregulation of GM3S in cells treated with SNA. (c) The effect of SNA on healing of exuditing wounds in diabetic animals. (d) SEM images of mesoporous silicon nanoneedles. (e) Confocal image of cells over the nanoneedle arrays. (f,g) Effect of VEGF-165 gene delivery on vascularization *in vivo*. Figures are reproduced with permission from references [216] and [218].

**Figure 8**
Stimuli responsive self responding drug delivery systems. (a) Stimuli responsible for swelling of hydrogels for controlling drug delivery. (b) pH responsive hydrogels of agarose/tannic acid crosslinked with zinc ions for the automatic release of tannic acid as an antibacterial and anti-inflammatory drug. (c) The mechanism of action dextrin–rhEGF conjugates in the wound. (d) Effect of α-amylase on the activity of rhEGF. (e) Stability of free rhEGF and dextrin-rhEGF in presence of neutrophil elastase. Figures are reproduced with permission from references [236] and [243].

**Figure 9**
Externally triggered thermoresponsive drug delivery platforms for wound care. (a) A photograph and micrograph of thermoresponsive drug carriers encapsulated in an alginate layer casted on a flexible heater. (b,c) The effect of temperature on the response of the engineered thermoresponsive particles and the release of encapsulated compounds (c). (d) The effect of polymer concentration of the changes of the diameter of thermoresponsive particles. (e) The release profile of FTIC-dextran as a model molecule. (f,g) Nanofibrous meshes in which thermoresponsive nanocarriers were embedded within the nanofibers. A flexible heater was directly sputterd on the nanofibrous mesh. (h,i) Cumulative release of cefazolin from the engineered nanofibrous platform in response of continuous (h) and cyclic (i) application of heat. Figures are reproduced with permission from references [246] and [247].

**Figure 10**
Active delivery of different drugs and oxygen to wounds. (a) Schematics of a thread-based patch for the transdermal drug delivery in which each fiber was comprised of a core heater coated by a layer of hydrogel carrying thermoresponsive particles. The fibers were individually addressed. (b) Schematic of the engineered multi-compartment fibers in which cotton thread was coated with a conductive ink as a core, and covered with drug-loaded hydrogel. (c) Numerical simulation showing the temperature distribution when two fibers are triggered. (d) The release profile of cefazolin from the fibers at different temperatures. (e) The effect of number of activated fibers on cefazolin release from a textile patch. (f) An optical image of the patch on the wound model. (g) The effect of VEGF delivery from the patch on granulation tissue deposition. (h) Side view schematic of oxygen-releasing platform. (i) An image of a typical patch with multiple oxygen generation points. Figures are reproduced with permission from references [248] and [252].

**Figure 11**
Transdermal delivery of drugs using iontophoresis and liquid jet injectors. (a) Schematic showing the mechanism of operation iontophoretic drug delivery. (b) Schematic demonstrating the use of liquid jet injectors for delivery of drugs into skin. (c,d) The comparison of wound healing in wounded animals receiving prednisolone/HFG using jet injector (c) versus the control without receiving any therapies (d) 7 days post surgery. (e) The comparison of wound healing between groups receiving prednisolone/HFG using jet injector or regular hypodermic needles. The data showed better effectiveness of the jet injector in inducing wound healing. Figures are reproduced with permission from reference [259].

**Figure 12**
Smart and automated bandages for treatment of chronic wounds. (a) Schematic of multi-layer dressing with both sensing and drug delivery. The onboard electronics can process the data and trigger the drug delivery if needed. (b) A photograph of the wearable bandage with both sensing and drug delivery capabilities. (c) Schematic of a 3D printed bandage with colorimetric pH sensor and drug delivery capability. (d) Effect of bacterial culture on the color of the engineered bandage. Figures are reproduced with permission from references [265] and [77].

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References

1. Singer AJ, Clark RA. Cutaneous wound healing. New England journal of medicine. 1999;341:738–746. - PubMed
1. Frykberg RG, Banks J. Challenges in the Treatment of Chronic Wounds. Advances in Wound Care. 2015;4:560–582. - PMC - PubMed
1. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair and Regeneration. 2009;17:763–771. - PMC - PubMed
1. Fife CE, Carter MJ. Wound care outcomes and associated cost among patients treated in US outpatient wound centers: data from the US wound registry. Wounds: a compendium of clinical research and practice. 2012;24:10–17. - PubMed
1. Richmond NA, Lamel SA, Davidson JM, Martins-Green M, Sen CK, Tomic-Canic M, Vivas AC, Braun LR, Kirsner RS. US–National Institutes of Health-funded research for cutaneous wounds in 2012. Wound Repair and Regeneration. 2013;21:789–792. - PubMed

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[1] Singer AJ, Clark RA. Cutaneous wound healing. New England journal of medicine. 1999;341:738–746. - PubMed

[2] Singer AJ, Clark RA. Cutaneous wound healing. New England journal of medicine. 1999;341:738–746. - PubMed

[3] Frykberg RG, Banks J. Challenges in the Treatment of Chronic Wounds. Advances in Wound Care. 2015;4:560–582. - PMC - PubMed

[4] Frykberg RG, Banks J. Challenges in the Treatment of Chronic Wounds. Advances in Wound Care. 2015;4:560–582. - PMC - PubMed

[5] Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair and Regeneration. 2009;17:763–771. - PMC - PubMed

[6] Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair and Regeneration. 2009;17:763–771. - PMC - PubMed

[7] Fife CE, Carter MJ. Wound care outcomes and associated cost among patients treated in US outpatient wound centers: data from the US wound registry. Wounds: a compendium of clinical research and practice. 2012;24:10–17. - PubMed

[8] Fife CE, Carter MJ. Wound care outcomes and associated cost among patients treated in US outpatient wound centers: data from the US wound registry. Wounds: a compendium of clinical research and practice. 2012;24:10–17. - PubMed

[9] Richmond NA, Lamel SA, Davidson JM, Martins-Green M, Sen CK, Tomic-Canic M, Vivas AC, Braun LR, Kirsner RS. US–National Institutes of Health-funded research for cutaneous wounds in 2012. Wound Repair and Regeneration. 2013;21:789–792. - PubMed

[10] Richmond NA, Lamel SA, Davidson JM, Martins-Green M, Sen CK, Tomic-Canic M, Vivas AC, Braun LR, Kirsner RS. US–National Institutes of Health-funded research for cutaneous wounds in 2012. Wound Repair and Regeneration. 2013;21:789–792. - PubMed

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Drug delivery systems and materials for wound healing applications

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Drug delivery systems and materials for wound healing applications

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