Pharmaceutics

Research

20 pages, 2995 KiB

Open AccessArticle

Lignin-Based Nanoparticles as Both Structural and Active Elements in Self-Assembling and Self-Healing Multifunctional Hydrogels for Chronic Wound Management

by A. Gala Morena, Sílvia Pérez-Rafael and Tzanko Tzanov

Pharmaceutics 2022, 14(12), 2658; https://doi.org/10.3390/pharmaceutics14122658 - 30 Nov 2022

Cited by 7 | Viewed by 2136

Abstract

Efficient wound healing is feasible when the dressing materials simultaneously target multiple factors causing wound chronicity, such as deleterious proteolytic and oxidative enzymes and bacterial infection. Herein, entirely bio-based multifunctional self-assembled hydrogels for wound healing were developed by simply mixing two biopolymers, thiolated [...] Read more.

Efficient wound healing is feasible when the dressing materials simultaneously target multiple factors causing wound chronicity, such as deleterious proteolytic and oxidative enzymes and bacterial infection. Herein, entirely bio-based multifunctional self-assembled hydrogels for wound healing were developed by simply mixing two biopolymers, thiolated hyaluronic acid (HA-SH) and silk fibroin (SF), with lignin-based nanoparticles (NPs) as both structural and functional elements. Sono-enzymatic lignin modification with natural phenolic compounds results in antibacterial and antioxidant phenolated lignin nanoparticles (PLN) capable of establishing multiple interactions with both polymers. These strong and dynamic polymer-NP interactions endow the hydrogels with self-healing and shear-thinning properties, and pH-responsive NP release is triggered at neutral to alkaline pH (7–9). Despite being a physically crosslinked hydrogel, the material was stable for at least 7 days, and its mechanical and functional properties can be tuned depending on the polymer and NP concentration. Furthermore, human skin cells in contact with the nanocomposite hydrogels for 7 days showed more than 93% viability, while the viability of clinically relevant Staphylococcus aureus and Pseudomonas aeruginosa was reduced by 99.7 and 99.0%, respectively. The hydrogels inhibited up to 52% of the activity of myeloperoxidase and matrix metalloproteinases, responsible for wound chronicity, and showed a strong antioxidant effect, which are crucial features promoting wound healing. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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16 pages, 3886 KiB

Open AccessArticle

Semisolid Wet Sol–Gel Silica/Hydroxypropyl Methyl Cellulose Formulation for Slow Release of Serpin B3 Promotes Wound Healing In Vivo

by Mattia Albiero, Alice Fullin, Gianmarco Villano, Alessandra Biasiolo, Santina Quarta, Simone Bernardotto, Cristian Turato, Mariagrazia Ruvoletto, Gian Paolo Fadini, Patrizia Pontisso and Margherita Morpurgo

Pharmaceutics 2022, 14(9), 1944; https://doi.org/10.3390/pharmaceutics14091944 - 14 Sep 2022

Cited by 5 | Viewed by 2097

Abstract

Foot ulcerations are a disabling complication of diabetes and no treatment is currently available based on disease mechanisms. The protein serpin B3 (SB3) was identified as a positive biomarker of successful diabetic wound healing; therefore, its exogenous administration may promote healing. The topical [...] Read more.

Foot ulcerations are a disabling complication of diabetes and no treatment is currently available based on disease mechanisms. The protein serpin B3 (SB3) was identified as a positive biomarker of successful diabetic wound healing; therefore, its exogenous administration may promote healing. The topical administration of SB3 is challenging due to its protein nature. Physical entrapment in wet sol–gel silica can stabilize the protein’s conformation and permit its sustained delivery. However, irreversible syneresis and poor viscoelastic properties hamper wet sol–gel silica application as a semisolid vehicle. To overcome these limits, a sol–gel silica/hydroxypropylmethylcellulose (HPMC) hydrogel blend was developed. SB3 entrapped in 8% SiO₂ wet sol–gel silica preserved its structure, was stabilized against denaturation, and was slowly released for at least three days. Blending a silica gel with an HPMC–glycerol (metolose-G) hydrogel permitted spreadability without affecting the protein’s release kinetics. When administered in vivo, SB3 in silica/metolose-G—but not in solution or in metolose-G alone—accelerated wound healing in SB3 knockout and diabetic mouse models. The results confirmed that SB3 is a new pharmacological option for the treatment of chronic ulcers, especially when formulated in a slow-releasing vehicle. Silica–metolose-G represents a novel type of semisolid dosage form which could also be applied for the formulation of other bioactive proteins. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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14 pages, 1488 KiB

Open AccessArticle

Isolation of Aloe saponaria-Derived Extracellular Vesicles and Investigation of Their Potential for Chronic Wound Healing

by Manho Kim and Ju Hyun Park

Pharmaceutics 2022, 14(9), 1905; https://doi.org/10.3390/pharmaceutics14091905 - 08 Sep 2022

Cited by 21 | Viewed by 2752

Abstract

A chronic wound is caused by a failure to progress through the normal phases of wound repair in an orderly and timely manner. To induce skin regeneration while inhibiting chronic inflammation, numerous natural products, and in particular, plant-derived biomaterials, have been developed. Aloe [...] Read more.

A chronic wound is caused by a failure to progress through the normal phases of wound repair in an orderly and timely manner. To induce skin regeneration while inhibiting chronic inflammation, numerous natural products, and in particular, plant-derived biomaterials, have been developed. Aloe saponaria, is known to contain flavonoid and phenolic acid compounds with anti-oxidative and anti-inflammatory properties. Here, we isolated extracellular vesicles (EVs) from Aloe saponaria by polyethylene glycol (PEG)-based precipitation and investigated their potential as a therapeutic for chronic wound healing. The Aloe saponaria-derived EVs (AS-EVs) showed no significant cytotoxicity on several cell types, despite a high level of intracellular uptake. When lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were treated with AS-EVs, significant reductions in the expression of pro-inflammatory genes, such as interleukin-6 and interleukin-1β, were observed. Proliferation and migration of human dermal fibroblasts, as determined by the water-soluble tetrazolium salt-8 and transwell migration assay, respectively, were shown to be promoted by treatment with AS-EVs. It was also demonstrated that AS-EVs enhanced tube formation in human umbilical vein endothelial cells, indicating a stimulatory activity on angiogenesis; one of the crucial steps for effective wound healing. Collectively, our results suggest the potential of AS-EVs as a natural therapeutic for chronic wound healing. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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17 pages, 2941 KiB

Open AccessArticle

Transdermal Delivery of High Molecular Weight Antibiotics to Deep Tissue Infections via Droplette Micromist Technology Device (DMTD)

by Lakshmi Pulakat, Howard H. Chen, Madhavi P. Gavini, Lauren A. Ling, Yinian Tang, Alexander Mehm, Gregory L. Martin, Corinna N. Beale, Brian P. Mooney and Hongmin Sun

Pharmaceutics 2022, 14(5), 976; https://doi.org/10.3390/pharmaceutics14050976 - 30 Apr 2022

Cited by 1 | Viewed by 1938

Abstract

Wound infection by multidrug-resistant (MDR) bacteria is a major disease burden. Systemic administration of broad-spectrum antibiotics colistin methanesulfonate (CMS) and vancomycin are the last lines of defense against deep wound infections by MDR bacteria. However, systemic administration of CMS and vancomycin are linked [...] Read more.

Wound infection by multidrug-resistant (MDR) bacteria is a major disease burden. Systemic administration of broad-spectrum antibiotics colistin methanesulfonate (CMS) and vancomycin are the last lines of defense against deep wound infections by MDR bacteria. However, systemic administration of CMS and vancomycin are linked to life-threatening vital organ damage. Currently there are no effective topical application strategies to deliver these high molecular weight antibiotics across the stratum corneum. To overcome this difficulty, we tested if high molecular weight antibiotics delivered by Droplette micromist technology device (DMTD), a transdermal delivery device that generates a micromist capable of packaging large molecules, could attenuate deep skin tissue infections. Using green fluorescent protein-tagged E. coli and live tissue imaging, we show that (1) the extent of attenuation of deep-skin E. coli infection was similar when treated with topical DMTD- or systemic IP (intraperitoneal)-delivered CMS; (2) DMTD-delivered micromist did not spread the infection deeper; (3) topical DMTD delivery and IP delivery resulted in similar levels of vancomycin in the skin after a 2 h washout period; and (4) IP-delivered vancomycin was about 1000-fold higher in kidney and plasma than DMTD-delivered vancomycin indicating systemic toxicity. Thus, topical DMTD delivery of these antibiotics is a safe treatment for the difficult-to-treat deep skin tissue infections by MDR bacteria. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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21 pages, 5176 KiB

Open AccessArticle

Resveratrol Microencapsulation into Electrosprayed Polymeric Carriers for the Treatment of Chronic, Non-Healing Wounds

by Andrea De Pieri, Keegan Ocorr, Kyle Jerreld, Mikkael Lamoca, Wolfgang Hitzl and Karin Wuertz-Kozak

Pharmaceutics 2022, 14(4), 853; https://doi.org/10.3390/pharmaceutics14040853 - 13 Apr 2022

Cited by 3 | Viewed by 2177

Abstract

Chronic, non-healing wounds represent a challenging socio-economic burden, demanding innovative approaches for successful wound management. Resveratrol (RSV) represents a promising therapeutic candidate, but its therapeutic efficacy and clinical applicability have been hampered by its rapid degradation and/or depletion. Herein, RSV was encapsulated into [...] Read more.

Chronic, non-healing wounds represent a challenging socio-economic burden, demanding innovative approaches for successful wound management. Resveratrol (RSV) represents a promising therapeutic candidate, but its therapeutic efficacy and clinical applicability have been hampered by its rapid degradation and/or depletion. Herein, RSV was encapsulated into poly(ε-caprolactone) (PCL) microparticles by electrospraying with the aim to prolong and preserve RSV’s release/activity, without affecting its therapeutic properties. Electrospraying led to the fabrication of spherical (2 to 10 μm in size), negatively charged (<−1 mV), and quasi-monodisperse (PDI < 0.3) microparticles, with 60% RSV release after 28 days. Microencapsulation of RSV into PCL prevented its photochemical degradation and preserved its antioxidant properties over 72 h. The RSV-PCL microparticles did not exhibit any cytotoxicity on human dermal fibroblasts. RSV released from the microparticles was biologically functional and induced a significant increase in collagen type I deposition. Furthermore, the produced RSV-PCL microparticles reduced the expression of inflammatory (IL-6, IL-8, COX-2) and proteolytic (MMP-2, MMP-9) mediators. Collectively, our data clearly illustrate the potential of electrosprayed polymeric carriers for the sustained delivery of RSV to treat chronic wounds. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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21 pages, 2766 KiB

Open AccessArticle

Accelerated Wound Healing in Minipigs by On-Site Production and Delivery of CXCL12 by Transformed Lactic Acid Bacteria

by Emelie Öhnstedt, Hava Lofton Tomenius, Peter Frank, Stefan Roos, Evelina Vågesjö and Mia Phillipson

Pharmaceutics 2022, 14(2), 229; https://doi.org/10.3390/pharmaceutics14020229 - 19 Jan 2022

Cited by 11 | Viewed by 2328

Abstract

Non-healing wounds are a growing medical problem and result in considerable suffering. The lack of pharmaceutical treatment options reflects the multistep wound healing process, and the complexity of both translation and assessment of treatment efficacy. We previously demonstrated accelerated healing of full-thickness wounds [...] Read more.

Non-healing wounds are a growing medical problem and result in considerable suffering. The lack of pharmaceutical treatment options reflects the multistep wound healing process, and the complexity of both translation and assessment of treatment efficacy. We previously demonstrated accelerated healing of full-thickness wounds in mice following topical application of the probiotic bacteria Limosilactobacillus reuteri R2LC transformed to express CXCL12. In this study, safety and biological effects of a freeze-dried formulation of CXCL12-producing L. reuteri (ILP100) were investigated in induced full-thickness wounds in minipigs, and different wound healing evaluation methods (macroscopic, planimetry, 2D-photographs, 3D-scanning, ultrasound) were compared. We found that treatment with ILP100 was safe and accelerated healing, as granulation tissue filled wound cavities 1 day faster in treated compared to untreated/placebo-treated wounds. Furthermore, evaluation using planimetry resulted in 1.5 days faster healing than using 2D photographs of the same wounds, whereas the areas measured using 2D photographs were smaller compared to those obtained from 3D scans accounting for surface curvatures, whereas ultrasound imaging enabled detailed detection of thin epithelial layers. In conclusion, topical administration of the drug candidate ILP100 warrants further clinical development as it was proven to be safe and to accelerate healing using different evaluation methods in minipigs. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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16 pages, 6531 KiB

Open AccessArticle

Cerium-Containing Bioactive Glasses Promote In Vitro Lymphangiogenesis

by Hanyu Xie, Sha Sha, Lingbo Lu, Geng Wu, Hongbing Jiang, Aldo R. Boccaccini, Kai Zheng and Rongyao Xu

Pharmaceutics 2022, 14(2), 225; https://doi.org/10.3390/pharmaceutics14020225 - 19 Jan 2022

Cited by 7 | Viewed by 2137

Abstract

The lymphatic system is crucial for the regeneration of many tissues due to its fundamental role in immune cell trafficking, protein transport, and tissue homeostasis maintenance. Strategies stimulating lymphangiogenesis can provide new therapeutic approaches for tissue repair and regeneration (e.g., chronic wound healing). [...] Read more.

The lymphatic system is crucial for the regeneration of many tissues due to its fundamental role in immune cell trafficking, protein transport, and tissue homeostasis maintenance. Strategies stimulating lymphangiogenesis can provide new therapeutic approaches for tissue repair and regeneration (e.g., chronic wound healing). Here, we explored the effects of cerium-containing mesoporous bioactive glass nanoparticles (Ce-MBGNs) on lymphangiogenesis. The results showed that the extracts of Ce-MBGNs (1, 5, or 10 wt/v%) were non-cytotoxic toward lymphatic endothelial cells (LECs), while they enhanced the proliferation of LECs. Moreover, as evidenced by the scratch wound healing and Transwell migration assays, conditioned media containing the extract of Ce-MBGNs (1 wt/v%) could enhance the migration of LECs in comparison to the blank control and the media containing vascular endothelial growth factor-C (VEGF-C, 50 ng/mL). Additionally, a tube-formation assay using LECs showed that the extract of Ce-MBGNs (1 wt/v%) promoted lymphatic vascular network formation. Western blot results suggested that Ce-MBGNs could induce lymphangiogenesis probably through the HIF-1α/VEGFR-3 pathway. Our study for the first time showed the effects of Ce-MBGNs on stimulating lymphangiogenesis in vitro, highlighting the potential of Ce-MBGNs for wound healing. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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18 pages, 2758 KiB

Open AccessArticle

Skin Substitute Preparation Method Induces Immunomodulatory Changes in Co-Incubated Cells through Collagen Modification

by Jordan Holl, Cezary Pawlukianiec, Javier Corton Ruiz, Dawid Groth, Kamil Grubczak, Hady Razak Hady, Jacek Dadan, Joanna Reszec, Slawomir Czaban, Cezary Kowalewski, Marcin Moniuszko and Andrzej Eljaszewicz

Pharmaceutics 2021, 13(12), 2164; https://doi.org/10.3390/pharmaceutics13122164 - 15 Dec 2021

Cited by 8 | Viewed by 3073

Abstract

Chronic ulcerative and hard-healing wounds are a growing global concern. Skin substitutes, including acellular dermal matrices (ADMs), have shown beneficial effects in healing processes. Presently, the vast majority of currently available ADMs are processed from xenobiotic or cadaveric skin. Here we propose a [...] Read more.

Chronic ulcerative and hard-healing wounds are a growing global concern. Skin substitutes, including acellular dermal matrices (ADMs), have shown beneficial effects in healing processes. Presently, the vast majority of currently available ADMs are processed from xenobiotic or cadaveric skin. Here we propose a novel strategy for ADM preparation from human abdominoplasty-derived skin. Skin was processed using three different methods of decellularization involving the use of ionic detergent (sodium dodecyl sulfate; SDS, in hADM 1), non-ionic detergent (Triton X-100 in hADM 2), and a combination of recombinant trypsin and Triton X-100 (in hADM 3). We next evaluated the immunogenicity and immunomodulatory properties of this novel hADM by using an in vitro model of peripheral blood mononuclear cell culture, flow cytometry, and cytokine assays. We found that similarly sourced but differentially processed hADMs possess distinct immunogenicity. hADM 1 showed no immunogenic effects as evidenced by low T cell proliferation and no significant change in cytokine profile. In contrast, hADMs 2 and 3 showed relatively higher immunogenicity. Moreover, our novel hADMs exerted no effect on T cell composition after three-day of coincubation. However, we observed significant changes in the composition of monocytes, indicating their maturation toward a phenotype possessing anti-inflammatory and pro-angiogenic properties. Taken together, we showed here that abdominoplasty skin is suitable for hADM manufacturing. More importantly, the use of SDS-based protocols for the purposes of dermal matrix decellularization allows for the preparation of non-immunogenic scaffolds with high therapeutic potential. Despite these encouraging results, further studies are needed to evaluate the beneficial effects of our hADM 1 on deep and hard-healing wounds. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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19 pages, 2859 KiB

Open AccessArticle

Preparation and Pharmacokinetic Characterization of an Anti-Virulence Compound Nanosuspensions

by Nan Wang, Feng Qi, Xiaolong He, Honglan Shi, David W. Anderson, Hao Li and Hongmin Sun

Pharmaceutics 2021, 13(10), 1586; https://doi.org/10.3390/pharmaceutics13101586 - 29 Sep 2021

Cited by 7 | Viewed by 2451

Abstract

Antibiotic resistance has become a worldwide public health threat due to the rapid evolution and spread of antibiotic-resistant bacteria. CCG-211790 is a novel anti-virulence compound that does not kill bacteria but could ameliorate human diseases by inhibiting expression of virulence factors, thereby applying [...] Read more.

Antibiotic resistance has become a worldwide public health threat due to the rapid evolution and spread of antibiotic-resistant bacteria. CCG-211790 is a novel anti-virulence compound that does not kill bacteria but could ameliorate human diseases by inhibiting expression of virulence factors, thereby applying less selection pressure for antibiotic resistance. However, its potential clinical use is restricted because of its poor aqueous solubility, resulting in formulation challenges. Nanosuspension technology is an effective way to circumvent this problem. Nanosuspensions of CCG-211790 with two different particle sizes, NanoA (315 ± 6 nm) and NanoB (915 ± 24 nm), were prepared using an antisolvent precipitation-ultrasonication method with Tween 80 as the stabilizer. Particle and pharmacokinetics (PK) of CCG-211790 nanosuspensions were characterized. Both NanoA and NanoB demonstrated remarkable increases in dissolution rate compared with the bulk compound. The PK parameters of NanoA were comparable to those of CCG-211790 solution formulation in intravenous or oral administration, suggesting that CCG-211790 nanosuspensions with smaller particle size improved oral bioavailability and drug exposure compared to traditional formulations of drug candidates. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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Review

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25 pages, 9173 KiB

Open AccessReview

Extracellular Vesicles as Therapeutic Tools for the Treatment of Chronic Wounds

by Eric R. Bray, Alisha R. Oropallo, Daniel A. Grande, Robert S. Kirsner and Evangelos V. Badiavas

Pharmaceutics 2021, 13(10), 1543; https://doi.org/10.3390/pharmaceutics13101543 - 23 Sep 2021

Cited by 23 | Viewed by 3537

Abstract

Chronic wounds develop when the orderly process of cutaneous wound healing is delayed or disrupted. Development of a chronic wound is associated with significant morbidity and financial burden to the individual and health-care system. Therefore, new therapeutic modalities are needed to address this [...] Read more.

Chronic wounds develop when the orderly process of cutaneous wound healing is delayed or disrupted. Development of a chronic wound is associated with significant morbidity and financial burden to the individual and health-care system. Therefore, new therapeutic modalities are needed to address this serious condition. Mesenchymal stem cells (MSCs) promote skin repair, but their clinical use has been limited due to technical challenges. Extracellular vesicles (EVs) are particles released by cells that carry bioactive molecules (lipids, proteins, and nucleic acids) and regulate intercellular communication. EVs (exosomes, microvesicles, and apoptotic bodies) mediate key therapeutic effects of MSCs. In this review we examine the experimental data establishing a role for EVs in wound healing. Then, we explore techniques for designing EVs to function as a targeted drug delivery system and how EVs can be incorporated into biomaterials to produce a personalized wound dressing. Finally, we discuss the status of clinically deploying EVs as a therapeutic agent in wound care. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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Other

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22 pages, 640 KiB

Open AccessSystematic Review

Effectiveness of Copper Nanoparticles in Wound Healing Process Using In Vivo and In Vitro Studies: A Systematic Review

by Cristian Sandoval, Gemima Ríos, Natalia Sepúlveda, Jessica Salvo, Vanessa Souza-Mello and Jorge Farías

Pharmaceutics 2022, 14(9), 1838; https://doi.org/10.3390/pharmaceutics14091838 - 31 Aug 2022

Cited by 15 | Viewed by 3977

Abstract

Chronic wounds are defined as wounds that do not heal in an orderly and timely manner through the various stages of the healing process. Copper nanoparticles are essential in dressings for wound healing because they promote angiogenesis and skin regeneration, which hasten the [...] Read more.

Chronic wounds are defined as wounds that do not heal in an orderly and timely manner through the various stages of the healing process. Copper nanoparticles are essential in dressings for wound healing because they promote angiogenesis and skin regeneration, which hasten the healing process. This systematic investigation sought to explain how copper nanoparticles affect chronic wound healing in vivo and in vitro. We realized a systematic review of original articles studying the effectiveness of copper nanoparticles in the healing process of chronic wounds. The protocol was registered in the PROSPERO database. Several databases were searched between 2012 and January 2022 for English-language papers using MeSH terms and text related to chronic wounds, copper nanoparticles, and wound healing. Quality was evaluated using National Institute for Health and Care Excellence methodology and PRISMA guidelines. We looked at a total of 12 primary studies. Quantitative data were gathered and presented in all studies. Our results suggest that copper nanoparticles could have an excellent healing property, facilitating the liberation of growth factors that help the anti-inflammatory process of the wound and significantly improving antibacterial and antioxidant activities. In addition, copper presents a higher biocompatibility than other metallic ions, promoting regeneration and increasing skin quality. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds)

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