Low-adhesion and low-swelling hydrogel based on alginate and carbonated water to prevent temporary dilation of wound sites.

Hydrogel-based wound dressings have been developed for rapid wound healing; however, their adhesive properties have not been adequately investigated. Excessive adhesion to the skin causes wound expansion and pain when hydrogels absorb exudates and swell at wound sites. Herein, we developed a low-adhesion and low-swelling hydrogel dressing using alginate, which is non-adhesive to cells and skin tissue, CaCO3, and carbonated water. The alginate/CaCO3 solution rapidly formed a hydrogel upon the addition of carbonated water, and the CO2 in the hydrogel diffused into the atmosphere, preventing acidification and obtaining a pH value suitable for wound healing. Remarkably, the skin adhesion and swelling of the hydrogel were 11.9- to 16.5-fold and 1.9-fold lower, respectively, than those of clinical low-adhesion hydrogel dressings. In vivo wound-healing tests in mice demonstrated its therapeutic efficacy, and the prepared hydrogel prevented temporary wound dilation during early healing. These results illustrate the importance of controlling skin adhesion and swelling in wound dressings and demonstrate the potential clinical applications of this wound-friendly hydrogel dressing.

Physicochemical Properties of Egg-Box-Mediated Hydrogels with Transiently Decreased pH Employing Carbonated Water.

Anionic polysaccharides, including low-methoxy (LM) pectin, are extensively used in biomaterial applications owing to their safety, biocompatibility, and feasibility in constructing supramolecular assemblies by forming egg-box structures with divalent cations. Mixing an LM pectin solution with CaCO3 spontaneously forms a hydrogel. The gelation behavior can be controlled by adding an acidic compound to change the solubility of CaCO3. CO2 is used as the acidic agent and can be easily removed after gelation, thereby reducing the acidity of the final hydrogel. However, CO2 addition has been controlled under varied thermodynamical conditions; therefore, specific CO2 effects on gelation are not necessarily visualized. To evaluate the CO2 impact on the final hydrogel, which would be extended to control hydrogel properties further, we utilized carbonated water to supply CO2 into the gelation mixture without changing its thermodynamic conditions. The addition of the carbonated water accelerated gelation and significantly increased the mechanical strength, promoting cross-linking. However, the CO2 volatilized into the atmosphere, and the final hydrogel became more alkaline than that without the carbonated water, probably because a considerable amount of the carboxy group was consumed for cross-linking. Moreover, when aerogels were prepared from the hydrogels with carbonated water, they exhibited highly ordered networks of elongated porosity in scanning electron microscopy, proposing an intrinsic structural change by CO2 in the carbonated water. We also controlled the pH and strength of the final hydrogels by changing the CO2 amounts in the carbonated water added, thereby validating the significant effect of CO2 on hydrogel properties and the feasibility of using carbonated water.

Preparation and Evaluation of Hydrogel Film Containing Tramadol for Reduction of Peripheral Neuropathic Pain.

To develop and assess new dosage forms for the alternative to existing oral medication for peripheral neuropathy, a hydrogel film in the skin patch formation containing tramadol hydrochloride (TRA), a water-soluble drug used as an analgesic, was prepared and evaluated. A hydrogel film composed of 20%(w/w) hydroxypropyl methylcellulose (HPMC) irradiated with electron beams had high transparency and elasticity similar to commercially available wound dressings and soft tissues, suggesting that it is a suitable substrate for TRA. The inclusion of TRA was enabled by immersing the HPMC hydrogel film in TRA aqueous solution. The release and skin permeation of TRA from TRA-containing hydrogel films differed depending on the electron beam dose. Moreover, the analgesic effects in mice were confirmed in a dose-dependent manner. This study demonstrated the usefulness of a hydrogel film containing TRA as a new dosage form alternative to the existing oral medication for peripheral neuropathy.

Evaluation of nephrotoxicity and ototoxicity following amikacin administration once daily or every 48 hours in neonates.

The purpose of this study was to evaluate the effects of once daily (OD) or every 48 hours (every-48-h) administration of amikacin (AMK) on renal function and ototoxicity in neonates. We investigated the frequency of nephrotoxicity and ototoxicity in neonates who received AMK OD or every-48-h from April 2015 to March 2021 and underwent dose evaluation by therapeutic drug monitoring (TDM). In addition, the relationships among birth weight, gestational age, AMK peak and trough values, total duration of AMK administration, and total AMK dose were examined separately for nephrotoxicity and ototoxicity. AMK was administered OD in 38 patients and every-48-h in 62 patients. Nephrotoxicity was observed in 8 patients on OD versus 36 patients on every-48-h administration (P < .001), and ototoxicity was observed in 2 patients on OD versus 12 patients on every-48-h administration (P = .192). For nephrotoxicity, only the trough value was relevant (P = .007). In terms of ototoxicity, there were no influencing factors. The risk of nephrotoxicity was higher with every-48-h AMK administration than with OD AMK administration, with nephrotoxicity depending on the trough value. However, compared with OD, the every-48-h group had lower body weight and possibly poorer original renal function. In addition, ototoxicity did not differ by administration method. Based on these results, every-48-h administration of AMK can be used as safely as OD by performing TDM and preventing high concentrations.

Microparticulated Mefenamic Acid with High Dispersion Stability for Pediatric Dosage Form.

Mefenamic acid (MFA), a water-insoluble drug, is used as a suspension in the medical field, but it requires shaking before using to disperse MFA content in the suspension. In previous studies, trials to prepare MFA suspension with high dispersion stability by atomizing MFA by the wet-milling method. However, HPC is used for atomizing MFA. Therefore, the optimum concentration and molecular weight for atomizing MFA have not been investigated. In this study, we investigated the optimum molecular weight and concentration of HPC for the micronization of MFA. As a result, MFA particles became fine particles by adding SDS, and the particle size was also smaller than that of HPC alone. In addition, the suspension with the highest dispersion stability can be obtained when a mixed solution of 1.0% HPC-SL and 0.12% SDS aqueous solution is used. Therefore, this study considers that the addition of SDS and 1.0% HPC-SL aqueous solution are optimal for improving the dispersion stability of the MFA suspension.

Saturated adsorption of lidocaine and coal tar dyes onto porous polytetrafluoroethylene.

Polytetrafluoroethylene (PTFE) has excellent physical properties and has been used in a wide range of applications in various fields. Adsorption research on PTFE is essential as primary research for the further application of PTFE. We attempted to adsorb coal tar dyes and model drugs such as lidocaine onto PTFE as a guideline to search for medicines that adsorb onto PTFE. Saturation curves were obtained after analyzing the adsorption of coal tar dyes on PTFE using the Hanes-Woolf plot. In addition, we collected multiple cases of ATR-FTIR spectral changes and/or retention depending on TPM derivatives and other adsorbates. Lidocaine matched some coal tar dye for the apparent spectral changes between the adsorbed molecules and its crystalline powder. The apparent spectral changes are blue-shifted, suggesting a hydrophobic interaction between the dyes/lidocaine and porous PTFE. This work provides a promising strategy for further application of PTFE.

Index for the appropriate vancomycin dosing in premature neonates and infants.

BACKGROUND: In neonates, vancomycin (VCM) is used to treat Gram-positive bacterial infections. However, VCM blood concentrations are affected by gestational age, bodyweight (BW), and renal function. The initial VCM dose adjustment can therefore be difficult, and few reports have evaluated this issue. In this study, we investigated the factors determining the appropriate VCM dosing schedule in neonates, especially premature infants. METHODS: The VCM dosage and trough concentrations were retrospectively investigated from the initial treatment to maintenance therapy in neonatal intensive care unit patients who underwent therapeutic drug monitoring. We examined the average single-administration VCM dosage during maintenance therapy. We then compared the actual VCM dose with that calculated using an index comprising six items that influence the VCM daily dose (postnatal age, gestational age, BW, serum creatinine level, urine output, and lactate level). RESULTS: Twenty premature infants were included. The average BW of patients at the initial VCM administration was 975 g. During maintenance therapy, the average VCM dose was 8.4 mg/kg, and the median trough concentration was 12.4 µg/mL. When we applied the six-item index, 18 of 20 patients (90%) had concordant results between the actual VCM dosing schedule and the VCM calculated using the index. CONCLUSIONS: The average VCM dose and six-item index can facilitate the transition from the initial VCM dose to an appropriate dose in many cases and contribute to early treatment in low-birthweight infants with more variable BW, distribution volumes, and renal function. In conclusion, our six-item index may help standardize VCM administration in premature infants.

The Role for miR-146b-5p in the Attenuation of Dermal Fibrosis and Angiogenesis by Targeting PDGFRα in Skin Wounds.

As a candidate microRNA antifibrotic effector in skin wounds, miR-146b-5p was upregulated by basic FGF, and PDGFRα was identified as a direct target of miR-146b-5p in fibroblasts. The treatment of fibroblasts with a miR-146b-5p mimic markedly downregulated the expression of PDGFRα and collagen type I. miR-146b-5p mimic transfection in wounds markedly attenuated cutaneous fibrosis, whereas a miR-146b-5p inhibitor strongly promoted fibrosis, with increases in PDGFRα and collagen I levels. These results indicate the positive effects of miR-146b-5p for the suppression of fibrosis, possibly through the inhibition of PDGFRα. The miR-146b-5p inhibitor markedly increased CD34+ vessel numbers and CD34 expression in wounds. We found miR-146b-5p+ cells in close contact with S100+ adipocytes. Moreover, we discovered the specific colocalization of the exosome marker CD81 and miR-146b-5p in the adipose tissue cells of mimic-transfected wounds, with miR-146b-5p signals being detected in the FSP1+ fibroblastic cells of adipose tissues. Therefore, fibroblastic cells of adipose tissues, which may specifically pick up and contain miR-146b-5p by exosome after transfection, may play an important role in the suppression of fibrosis. In this process, the inhibition of PDGFRα in adipose tissue cells by miR-146b-5p may lead to the loss of their PDGFRα-induced profibrotic activities, thereby suppressing fibrosis.

Preparation and Evaluation of a Powdered Rebamipide Mouthwash as In-Hospital Formulation: Considering Dispersion before Use in Patients.

In Japan, rebamipide (RB) mouthwash (RB-MW) for oral mucositis induced by cancer chemotherapy has been prepared using in-hospital formulation. Usually, RB-MW is prepared by dispersing crushed commercial RB tablets in the dispersion medium; however, uniformity is difficult to obtain due to low solubility. The current study aims is to prepare homogenously dispersed formulations using the fine particles of crushed tablets by a method that is convenient for hospital use. Commercial RB tablets were pre-milled at different milling times as "RB-Ts". A ground mixture was then prepared by co-grinding the RB-Ts with HPC-L or PVP K30 via a benchtop ball milling machine (MM400). The physicochemical properties of samples were evaluated for PXRD, FTIR, turbidity, particle size, and solubility. Although the milling of RB tablets decreased the crystallinity, the length of milling time did not affect them. In contrast, grinding using MM400 significantly decreased RB crystallinity; their PXRD patterns showed a halo, suggesting the amorphization of RB crystals by grinding. Although solubility and turbidity seemed to be affected by the type of polymer rather than the particle size, every ground mixture showed high dispersibility. Thus, grinding the RB-Ts with polymers appeared to be the most promising way to obtain stable dispersion as an in-hospital formulation.

Solubility Enhancement of Ibuprofen by Adsorption onto Spherical Porous Calcium Silicate.

The solubility of a drug is higher when it is in an amorphous form than when it is in a crystalline form. To enhance the solubility of ibuprofen (IBU), a poorly water-soluble drug, we attempted to adsorb IBU onto spherical porous calcium silicate (Florite® PS300, PS300) in two ways: the evaporation (EV) and sealed heating (SH) methods. The crystallinity of the samples was evaluated using powder X-ray diffraction analysis (PXRD) and differential scanning calorimetry (DSC). The molecular interaction between IBU and PS300 was evaluated with FTIR. In addition, the dissolution behavior of IBU in the samples was assessed by the dissolution test. Based on the results of the PXRD and DSC measurements, both methods allowed adsorption of IBU onto PS300, and IBU was amorphized. Based on the FTIR observations, in the SH or EV mixtures containing 10% and 30% IBU, respectively, it seemed that the IBU molecules intermolecularly interacted with calcium molecules as the main component of PS300. Improvement in the solubility of IBU was observed with both methods; however, the dissolution rate of IBU from samples prepared via SH was higher than that from EV, or of IBU crystals. Collectively, our findings indicate that the petal-like structure of PS300, which has a spherical shape and good flowability, is an effective tool for adsorbing IBU onto PS300 via SH.

Wound Healing Promotion by Hyaluronic Acid: Effect of Molecular Weight on Gene Expression and In Vivo Wound Closure.

Hyaluronic acid (HA) has been known to play an important role in wound healing process. However, the effect of molecular weight (MW) of exogenously administered HA on the wound healing process has not been fully understood. In this study, we investigated HA with different MWs on wound healing process using human epidermal keratinocytes and dermal fibroblasts. Cell proliferation and migration ability were assessed by water soluble tetrazolium (WST) assay and wound scratch assay. We examined the effect of HA addition in a full-thickness wound model in mice and the gene expression related to wound healing. Proliferation and migration of HaCaT cells increased with the increase of MW and concentration of HA. Interleukin (IL-1ß), IL-8 and vascular endothelial growth factor (VEGF) as well as matrix metalloproteinase (MMP)-9 and MMP-13 were significantly upregulated by high molecular weight (HMW) HA in keratinocytes. Together with VEGF upregulation and the observed promotion of HaCaT migration, HA with the MW of 2290 kDa may hold potential to improve re-epithelialization, a critical obstacle to heal chronic wounds.

Testing a Benchtop Wet-Milling Method for Preparing Nanoparticles and Suspensions as Hospital Formulations.

In clinical practice, for elderly or pediatric patients who have difficulty swallowing, solid dosage forms such as tablets or capsules are crushed or unsealed, prepared as powder forms, and often administered as suspensions. However, because their dispersibility is poor, aggregation or precipitation occurs readily. Once precipitation and deposition happen, redispersion is difficult, which can limit patient and caretaker drug adherence. In this study, we attempted to prepare nanoparticles as a hospital formulation by a benchtop wet-milling method to obtain a suspension with high dispersibility. This is the first study to apply the wet-milling method to prepare the hospital formulation. We chose cefditoren pivoxil (CDTR-PI) as an experimental active pharmaceutical ingredient. CDTR-PI crystals were physically mixed with various water-soluble polymers such as polyvinylpyrrolidone, polyethylene oxide, hydroxypropyl cellulose, or hypromellose and wet-milled with a surface-active agent (sodium lauryl sulfate) under different conditions. The mean particle diameter of most of the samples was less than 200 nm. In FTIR spectra of ground samples, peak shifts suggesting inter- or intramolecular interactions between CDTR-PI and the other additive agents were not observed. Besides, the nanoparticle suspension had favorable dispersibility, as determined using a dispersion stability analyzer. Providing a suspension with high dispersibility makes dispense with the resuspension, the patient's medication adherence would improve. These results show that suspended liquid formulations of active pharmaceutical ingredients could be obtained by the simple wet-milling method as hospital formulations.

A novel hydrogel sheet prevents postoperative pancreatic fistula in a rat model.

AIM: To evaluate the efficacy of a novel hydrogel sheet in preventing postoperative pancreatic fistula (POPF). BACKGROUND: Postoperative pancreatic fistula is a life-threatening complication. As no study has reported the use of hydrogel sheets in preventing POPF, their effectiveness for that purpose remains unclear. METHODS: A novel hydrogel sheet made of polyvinyl alcohol (PVA) was prepared by the freeze-thaw method. The pancreatic ducts and surrounding pancreatic parenchyma of rats were transected to induce a pancreatic fistula. Next, the sheet was attached to the transection site. Ascitic fluid amylase and lipase concentrations were measured. Neoveil® , a nonwoven polyglycolic acid (PGA) felt, is already clinically used as an absorbable reinforcing material at pancreatic transection sites. Neoveil® was used for comparison, as was VIEWGEL® , which is marketed as a wound dressing. RESULTS: The hydrogel sheet remained in place 48 hours postoperatively. The ascitic amylase concentrations in the control, VIEWGEL® -treated, Neoveil® -treated, and hydrogel-treated rats, respectively, were 4992.4 ± 5355.7, 1068.4 ± 269.1, 730.2 ± 425.2, and 303.1 ± 240.1 IU/L; the ascitic lipase concentrations were 2279.8 ± 3395.2, 169.5 ± 100.6, 90.4 ± 71.0, and 86.8 ± 59.8 IU/L. The ascitic amylase and lipase levels were significantly lower in the hydrogel group than in the other groups (P < .05). CONCLUSIONS: This novel hydrogel sheet effectively prevents pancreatic fistulas and has promising clinical application potential.

Preparation and Characterization of Solid Dispersions Composed of Curcumin, Hydroxypropyl Cellulose and/or Sodium Dodecyl Sulfate by Grinding with Vibrational Ball Milling.

Solubility is an important physicochemical property affecting drug bioavailability. One approach to improve drug solubility is using amorphous formulations, which can improve solubility by up to a 1000-fold. Herein, amorphous curcumin (CUR) and amorphous solid dispersions (SDs) consisting of CUR, hydroxypropyl cellulose (HPC) and/or sodium dodecyl sulfate (SDS) were developed using vibrational ball milling. The resulting ground mixtures (GMs) were characterized using powder X-ray diffractometry, Fourier transform infrared spectroscopy, differential scanning calorimetry and a dissolution test. The 60-min GM containing 90% HPC significantly increased the drug solubility. Presence of SDS in the GMs containing 90% HPC reduced the grinding duration from 60 min to 30 min in forming a ground SD that significantly increased the CUR dissolution rate. This amorphous state was stable for 30 days when stored at 40 °C/RH 75%.

Enhancing the Solubility of Curcumin Using a Solid Dispersion System with Hydroxypropyl-ß-Cyclodextrin Prepared by Grinding, Freeze-Drying, and Common Solvent Evaporation Methods.

Cyclodextrins (CDs) and their derivatives significantly increase drug solubility by forming drug/CD complexes known as solid dispersions (SDs), which consist of an inclusion complex (IC), where the drug is entrapped within the CD cavity, and a non-IC. Here, the SDs of curcumin (CUR) and hydroxypropyl-ß-cyclodextrin (HPßCD) were prepared using the grinding, freeze-drying (FD), and common solvent evaporation (CSE) methods and were physicochemically characterized using solubility, powder X-ray diffraction, Fourier transform infrared, differential scanning calorimetry, and dissolution studies. The second or higher order complex of CUR-HPßCD indicated the co-existence of ICs and non-ICs known as the SD system. When comparing the soluble drug amount with CUR crystals, the solubility of SDs was enhanced by up to 299-, 180-, and 489-fold, corresponding to the ground mixtures (GMs), freeze-drying mixtures (FDs), and common solvent evaporation mixtures (CSEs), respectively. The total transformation into the amorphous phase of CUR was observed in GMs and in CSE12, CSE14, and CSE18. The drug was well dispersed within HPßCD in GMs and CSEs, suggesting the formation of hydrogen bonds between CUR and HPßCD, whereas the dispersed behavior of FDs was similar to that of physical mixtures. In SDs, the melting temperature of CUR was in an increased order of CUR in 1:2 ICs, CUR in 1:1 ICs, and CUR crystals. The dissolution rate of CUR was positively improved as the amount of HPßCD in SDs increased. The SD system consisting of CUR and HPßCD significantly increased the drug solubility compared to ICs.

Preliminary Investigation of the Usability Characteristics Required for Wound Management Products by Semi-Structural Interview of Medical Staff.

Consideration of drug usability characteristics is important during the design process. Although many wound management products have been developed in recent years, there are few studies on their usability. We investigated the needs and characteristics of wound management products required by medical professionals, so as to consider these in future development projects. Semi-structured interviews were conducted in a group of healthcare professionals. Interview responses were analyzed based on thematic analysis. Four themes common to all facilities were secondary wounds, adaptability of materials, convenience, and physicochemical properties. Economic efficiency of medical care was found to be considered only at the hospital, and quality of life of patients was found to be considered only at the home palliative care clinic. Requirements for wound management products can be affected by participants' roles and their facility settings. However, there were needs common to all fields that all wound management products should aim to incorporate.

Adsorption of a poorly water-soluble drug onto porous calcium silicate by the sealed heating method.

To improve the bioavailability of orally-administered drug, solubilization of poorly water-soluble drug is important. The solubility of a drug in its amorphous form is known to be higher than in its crystalline form. In this study, we attempted to adsorb a sublimable drug onto porous calcium silicate (Florite®, FLR) or non-porous calcium silicate (NPCS) by the sealed heating (SH) method and evaporated (EV) method. Ibuprofen (IBU) was used as the poorly water-soluble, sublimable drug. The physicochemical properties of samples were investigated using powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and dissolution test. From the PXRD and DSC results, IBU crystals were adsorbed and amorphized by the SH and EV methods with FLR. From the results of FTIR, the shift to a higher frequency by the carbonyl stretching vibration band of IBU suggests an intermolecular interaction between IBU and FLR. In SH with FLR, improved solubilization was observed. IBU adsorbed onto FLR showed a greater dissolution rate than the IBU crystals or NPCS. Thus, the petal-like structure of FLR may be an effective method to adsorb IBU onto FLR using the SH method.

Effect of Polymers and Storage Relative Humidity on Amorphous Rebamipide and Its Solid Dispersion Transformation: Multiple Spectra Chemometrics of Powder X-Ray Diffraction and Near-Infrared Spectroscopy.

This study aimed to investigate the effect of polymers and storage relative humidity on amorphous rebamipide (RB) and its solid dispersion phase transformation using chemometrics based on multiple datasets. The amorphous RB was prepared using particle mixture and grinding methods with hydroxypropyl cellulose, polyvinylpyrrolidone, and sodium dodecyl sulfate. Prepared amorphous RB and solid dispersion samples were stored under a relative humidity of 30% and 75% for four weeks. Infrared spectra of the dispersion samples suggested that the hydrogen bond network was constructed among quinolinone, carbonyl acid, and amide of RB and other polymers. The dataset combining near-infrared (NIR) spectra and powder X-ray diffractograms were applied to principal component analysis (PCA). The relationship between diffractograms and NIR spectra was evaluated using loadings and the PCA score. The multiple spectra analysis is useful for evaluating model amorphous active pharmaceutical ingredients without a standard sample.

Synergistic Antinociceptive Activity of Tramadol/Acetaminophen Combination Mediated by µ-Opioid Receptors.

We investigated whether tramadol could suppress both neuropathic and inflammatory pain in mice at the same dose level. We also examined the effects of drugs metabolized by glucuronidase, such as acetaminophen (ACAP), indomethacin, probenecid, and valproate, on the antinociceptive activity of tramadol. The administration of 5.6 or 10 mg/kg tramadol suppressed cuff-induced mechanical allodynia, but 10 mg/kg tramadol did not suppress complete Freund's adjuvant (CFA)-induced mechanical allodynia. Although neither tramadol (10 mg/kg) nor ACAP (100 mg/kg) alone produced an antinociceptive effect, their combination suppressed CFA-induced mechanical allodynia. Moreover, pretreatment naloxone, an opioid receptor antagonist, significantly attenuated the antinociceptive effects induced by the combination of tramadol and ACAP and slowed gastrointestinal transit. Similar to ACAP, the combination of tramadol and probenecid or valproate, which has the potential to inhibit uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT), also suppressed the CFA-induced mechanical allodynia and slowed gastrointestinal transit. We concluded that tramadol was more beneficial for the treatment of neuropathic pain than inflammatory pain. Furthermore, the antinociceptive effects of the tramadol and ACAP combination were mediated by the µ-opioid receptor, and were thought to be related, at least in part, to the accumulation of the active metabolite, M1.

Are Antimicrobial Peptide Dendrimers an Escape from ESKAPE?

Significance: The crisis of antimicrobial resistance (AMR) increases dramatically despite all efforts to use available antibiotics or last resort antimicrobial agents. The spread of the AMR, declared as one of the most important health-related issues, warrants the development of new antimicrobial strategies. Recent Advances: Antimicrobial peptides (AMPs) and AMP dendrimers (AMPDs), as well as polymer dendrimers are relatively new and promising strategies with the potential to overcome drug resistance issues arising in ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) colonizing chronic wounds. Critical Issues: AMPs-AMPDs suffer from limited efficacy, short-lasting bioactivity, and concerns of toxicity. To circumvent these drawbacks, their covalent coupling to biopolymers and/or encapsulation into different drug carrier systems is investigated, with a special focus on topical applications. Future Directions: Scientists and the pharmaceutical industry should focus on this challenging subject to either improve the activity of existing antimicrobial agents or find new drug candidates. The focus should be put on the discovery of new drugs or the combination of existing drugs for a better synergy, taking into account all kinds of wounds and existing pathogens, and more specifically on the development of next-generation antimicrobial peptides, encompassing the delivery carrier toward improved pharmacokinetics and efficacy.