Poly­d,l­lactic acid­enhanced atrophic scar treatment via transdermal microjet drug delivery in Asians.

BACKGROUND: Acne vulgaris often results in permanent scars, with atrophic scars being the most common type and posing a significant therapeutic challenge due to their prevalence and impact on patients' quality of life. Various treatment options exist, including the use of poly-d,l-lactic acid delivered via different methods. OBJECTIVE: This study aimed to assess the efficacy and safety of poly-d,l-lactic acid delivered via laser-assisted needle-free microjet injection for treating atrophic scars. METHODS: Five Korean participants with atrophic facial scars were recruited. Poly-d,l-lactic acid solution was administered via the Mirajet system in five sessions, with clinical assessments conducted at baseline, before each session, and at 12-week and 22-week follow-ups. Outcome measures included the Global Aesthetic Improvement Scale and patient satisfaction scores. RESULTS: Positive results were observed at the 12-week and 22-week follow-ups, with high patient satisfaction and improvements in atrophic scars and skin texture. Mild discomfort and transient side effects were reported, with no adverse events observed during the follow-up period. CONCLUSION: Poly-d,l-lactic acid delivered by a laser-assisted needle-free microjet injector was judged to be effective for improving atrophic the facial area. Further research, particularly through randomized controlled trials, is needed to validate these findings and assess the longer-term safety and sustainability of outcomes.

Facial Skin Rejuvenation Using Poly- dl -Lactic Acid Injected With a Laser-Generated Needle-Free Microjet Injector.

BACKGROUND: A laser-induced needle-free microjet injector was developed for rapid, high-speed drug delivery of microliters into the skin. OBJECTIVE: This study evaluated the clinical rejuvenation effect of repeated dermal injections of the collagen simulator poly- dl -lactic acid (PDLA) using a laser-induced needle-free microjet injector. METHODS: Five PDLA injection sessions using a laser-induced needle-free microjet injector were conducted in patients concerned about aging skin. Facial uplifting, darkness, redness, roughness, pore size, subjective satisfaction, and side effects were evaluated before each session and 4 weeks after treatment completion. Histological evaluation was also performed with immunohistochemical staining of collagen and elastic fibers. RESULTS: The clinical results of 27 female patients were evaluated. The treatment resulted in a noticeable skin surface uplifting (0.711 ± 0.42 mm) and significant improvements in darkness ( p = .013), redness ( p = .009), and roughness ( p = .036), with no significant difference in the pore size ( p = .770). Patients were reported being satisfied with the overall therapeutic effects, despite mild and tolerable adverse effects. Histological findings revealed growth and thickening of collagen and elastic fibers, with marked increase in collagen I and III levels. CONCLUSION: Repeated dermal injections of PDLA using a laser-induced microjet injector offer excellent drug delivery, achieving high efficacy in skin rejuvenation, patient satisfaction, and safety.

Toward a solid microneedle patch for rapid and enhanced local analgesic action.

Analgesic creams find widespread application as adjuncts for localized anesthesia prior to surgical procedures. Nevertheless, the onset of analgesic action is protracted due to the skin barrier's inherent characteristics, which necessitates prolonged intervals of patient and clinician waiting, consequently impinging upon patient compliance and clinician workflow efficiency. In this work, a biodegradable microneedles (MNs) patch was introduced to enhance the intradermal administration of lidocaine cream to achieve rapid analgesia through a minimally invasive and conveniently accessible modality. The polylactic acid (PLA) MNs were mass-produced using a simple hot-pressing method and served the purpose of creating microchannels across the skin's surface for rapid absorption of lidocaine cream. Optical and electron microscopes were applied to meticulously scrutinize the morphology of the fabricated MNs, and the comprehensive penetration tests involving dynamometer tests, evaluation on porcine cadaver skin, artificial film, optical coherence tomography (OCT), transepidermal water loss, and analysis on rats' skins, demonstrated the robust mechanical strength of PLA MNs for successful intradermal penetration. The behavioral pain sensitivity tests on living rats using Von Frey hair filaments revealed that the MN-assisted lidocaine treatment expeditiously accelerated the onset of action from 40 to 10 min and substantially enhanced the efficacy of localized anesthesia. Furthermore, different treatment protocols encompassing the sequence of drug application relative to MN treatment, MN dimensions, and the frequency of MN insertions exhibited noteworthy influence on the resultant local anesthesia efficacy. Together, these results demonstrated that the lidocaine cream followed by diverse PLA MN treatments would be a promising strategy for rapid clinical local anesthesia with wide-ranging applications.

Subconjunctival injection of rapamycin-loaded polymeric microparticles for effective suppression of noninfectious uveitis in rats.

Noninfective uveitis is a major cause of vision impairment, and corticosteroid medication is a mainstay clinical strategy that causes severe side effects. Rapamycin (RAPA), a potent immunomodulator, is a promising treatment for noninfective uveitis. However, because high and frequent dosages are required, it is a great challenge to implement its clinical translation for noninfective uveitis therapy owing to its serious toxicity. In the present study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., polycaprolactone-poly (ethylene glycol)-polycaprolactone, PCEC) for efficient ocular delivery of RAPA via a subconjunctival injection route and investigated its therapeutic efficacy in an experimental autoimmune uveitis (EAU) rat model. RAPA-PCEC microparticles were fabricated using the emulsion-evaporation method and thoroughly characterized using scanning electron microscopy, fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The formed microparticles exhibited slow in vitro degradation over 28 days, and provided both in vitro and in vivo sustained release of RAPA over 4 weeks. Additionally, a single subconjunctival injection of PCEC microparticles resulted in high ocular tolerance. More importantly, subconjunctival injection of RAPA-PCEC microparticles significantly attenuated the clinical signs of EAU in a dose-dependent manner by reducing inflammatory cell infiltration (i.e., CD45+ cells and Th17 cells) and inhibiting microglial activation. Overall, this injectable microparticulate system may be promising vehicle for intraocular delivery of RAPA for the treatment of noninfective uveitis.

Effect of electrospun poly (L-lactide-co-caprolactone) and formulated porcine fibrinogen for diabetic foot ulcers.

Diabetic foot ulcers were a significant complication of diabetes and were accompanied by delayed wound healing. To compare the effect of topical application electrospun poly (L-lactide-co-caprolactone) and formulated porcine fibrinogen (PLCL/Fg) dressing with alginate dressing when treating diabetic foot ulcers (DFUs). A single-center, prospective, randomized, patient-blinded clinical trial was conducted from July 1, 2023, to December 26, 2023. The clinical trial registration was completed on August 28, 2023 (ClinicalTrials.gov Identifier: NCT06014437). The eligible patients with DFUs of 1-20 cm2 present for at least 1 month and with Wagner grade 1 or 2. They were randomized 1:1 to receive PLCL/Fg or alginate dressing. Participants received PLCL/Fg dressing 1-3 times per week or alginate dressing 3 times per week for 12 weeks. A total of 52 patients (33 men [63.5 %]; mean [SD] age, 63.1 [11.9] years; mean [SD] diabetes time, 8.3 [4.6] years) with DFUs were assessed for this study. The DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 3.8 [3.2] cm2) were randomized to receive either the PLCL/Fg dressing (n = 26) or the alginate dressing (n = 26) for as long as 12 weeks. In this study, the incidence of complete healing included 22 patients (91.7 %) in the PLCL/Fg group and 14 (63.6 %) in the alginate group during the 12-week treatment period (P = 0.003). The treatment-related adverse events that occurred were 5 (20.8 %) in the PLCL/Fg group and 4 (18.1 %) in the comparator group. In this randomized clinical trial, PLCL/Fg dressing showed beneficial effects in DFUs treatment of wound surface reduction and regulating the wound microenvironment.

Intra-articular hydrogel formulation prolongs the in vivo stability of Toll-like receptor antagonistic peptides for rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation that primarily affects joint tissue and requires frequent medication. Recently, we developed cyclic phage-display-derived inhibitory peptides (CPs), which act as Toll-like Receptor 4 antagonists. These CPs exhibited therapeutic efficacy against joint diseases by alleviating inflammatory factors. Nonetheless, CP exhibits in vivo instability and a short half-life. Therefore, this study sought to improve the in vivo stability of CP, thereby reducing the frequency of CP administration through the development of an injectable hydrogel depot formulation. To improve in vivo stability, CP was chemically conjugated to hyaluronic acid (HA-CP) and subsequently mixed into a temperature-sensitive hydrogel [methoxy polyethylene glycol-b-poly(ε-caprolactone)-ran-poly(lactide) (PC)] as an injectable depot (PC+(HA-CP)). For comparison, CP was physically mixed with HA and PC (PC+(HA+CP)). Both PC+(HA-CP) and PC+(HA+CP) were found to rapidly form depots upon injection into the joint space. Cell viability assays confirmed the non-toxic nature of PC+(HA-CP) and PC+(HA+CP), whereas both formulations exhibited inhibition of inflammatory factors. Furthermore, PC+(HA-CP) retained CP for a longer duration compared to PC+(HA+CP) in the presence of hyaluronidase and within the RA joint space. Following intra-articular injection, both the PC+(HA-CP) and PC+(HA+CP) depots exhibited reductions in RA symptoms, cartilage regeneration, and suppression of pro-inflammatory cytokine levels. Specifically, by extending the in vivo retention of CP, PC+(HA-CP) demonstrated superior RA treatment efficacy compared to PC+(HA+CP). In conclusion, intra-articular injection of PC+(HA-CP) was validated as an effective strategy for treating RA, owing to its ability to prolong the in vivo retention of CP. This approach holds promise for improving RA management and patient outcomes.

Polymeric nanofiber leveraged co-delivery of anti-stromal PAK1 inhibitor and paclitaxel enhances therapeutic effects in stroma-rich 3D spheroid models.

The role of tumor stroma in solid tumors has been widely recognized in cancer progression, metastasis and chemoresistance. Cancer-associated fibroblasts (CAFs) play a crucial role in matrix remodeling and promoting cancer cell stemness and resistance via reciprocal crosstalk. Residual tumor tissue after surgical removal as well as unresectable tumors face therapeutic challenges to achieve curable outcome. In this study, we propose to develop a dual delivery approach by combining p21-activated kinase 1 (PAK1) inhibitor (FRAX597) to inhibit tumor stroma and chemotherapeutic agent paclitaxel (PTX) to kill cancer cells using electrospun nanofibers. First, the role of the PAK1 pathway was established in CAF differentiation, migration and contraction using relevant in vitro models. Second, polycaprolactone polymer-based nanofibers were fabricated using a uniaxial electrospinning technique to incorporate FRAX597 and/or PTX, which showed a uniform texture and a prolonged release of both drugs for 16 days. To test nanofibers, stroma-rich 3D heterospheroid models were set up which showed high resistance to PTX nanofibers compared to stroma-free homospheroids. Interestingly, nanofibers containing PTX and FRAX597 showed strong anti-tumor effects on heterospheroids by reducing the growth and viability by > 90 % compared to either of single drug-loaded nanofibers. These effects were reflected by reduced intra-spheroidal expression levels of collagen 1 and α-smooth muscle actin (α-SMA). Overall, this study provides a new therapeutic strategy to inhibit the tumor stroma using PAK1 inhibitor and thereby enhance the efficacy of chemotherapy using nanofibers as a local delivery system for unresectable or residual tumor. Use of 3D models to evaluate nanofibers highlights these models as advanced in vitro tools to study the effect of controlled release local drug delivery systems before animal studies.

Poly (Lactic Acid) membrane and Sedum dendroideum extract favors the repair of burns in rats

Abstract Purpose: To evaluate the healing potential of the electrospinning membranes of Poly (Lactic Acid) (PLA) associated with Sedum dendroideum extract in burn injuries in rats. Methods: Seventy-five rats were submitted to burn injury on their back skin: (C) untreated; (F) with daily topical application of S. dendroideum extract; (M) with electrospinning membranes of PLA; (MF10) with electrospinning membranes of PLA with 10% S. dendroideum extract; (MF25) with electrospinning membranes of PLA with 25% S. dendroideum extract. Tissue samples were taken after 2, 6 and 14 days of the burn injury and were subjected to histomorfometric analysis of quantification of fibroblasts, collagen fibers, blood vessels, and inflammatory infiltrate Results: The histomorphometric analysis showed an increase in the number of fibroblasts, collagen fibers and blood vessels in the burns treated with membranes of PLA, associated or not with the 10% and 25% extract. The extract of S. dendroideum promoted the increase of collagen fibers. Conclusion: The electrospinning PLA membrane, isolated or associated with the S. dendrodeum extract, favored the healing of burn injuries in this experimental model, with an increase of fibroblasts, collagen fibers, and blood vessels. S. dendroideum isolated only stimulated the collagenesis.

Comparative study of peritoneal adhesions after intraperitoneal implantation in rats of meshes of polypropylene versus polypropylene/polyglecaprone versus polyester/porcine collagen

Abstract Purpose To Compare the extent and intensity of adhesions formed between the intra-abdominal organs and the intraperitoneal implants of polypropylene mesh versus polypropylene/polyglecaprone versus polyester/porcine collagen used for correction of abdominal wall defect in rats. Methods After the defect in the abdominal wall, thirty Wistar rats were placed in three groups (ten animals each) for intraperitoneal mesh implant: polypropylene group, polypropylene/polyglecaprone group, and polyester/porcine collagen group. The macroscopic evaluation of the extent and intensity of adhesions was performed 21 days after the implant. Results The polypropylene group had a higher statistically significant impairment due to visceral adhesions (p value = 0.002) and a higher degree of intense adherence in relation to polypropylene/polyglecaprone and polyester/porcine collagen groups (p value<0.001). The polyester/porcine collagen group showed more intense adhesions than the polypropylene/polyglecaprone group (p value=0.035). Conclusions The intraperitoneal implantation of polypropylene meshes to correct defects of the abdominal wall caused the appearance of extensive and firm adhesions to intra-abdominal structures. The use of polypropylene/polyglecaprone or polyester/porcine collagen tissue-separating meshes reduces the number and degree of adhesions formed.

Comparative study of fibrosis induced by Marlex®, Parietex Composite®, Vicryl® and Ultrapro® meshes1

Abstract Purpose: To evaluate the fibrosis induced by four different meshes: Marlex®, Parietex Composite®, Vicryl® and Ultrapro®. Methods: Histological cutouts of abdominal wall were analyzed with polarized light 28 days after the meshes implants and colorized by picrosirius to identify the intensity of collagen types I and III, and their maturation index. Results: When the four groups were compared, the total collagen area analyzed was bigger in groups A and D, with no difference between them. The collagen type I density was bigger in group A, with an average of 9.62 ± 1.0, and smaller in group C, with an average of 3.86 ± 0.59. The collagen type III density was similar in groups A, B and C, and bigger in group D. The collagen maturation index was different in each of the four groups, bigger in group A with 0.87, group B with 0.66, group D with 0.57 and group C with 0.33 (p = 0.0000). Conclusion: The most prominent fibrosis promotion in the given meshes was found on Marlex® (polypropylene mesh) and the Parietex Composite® (non-biodegradable polyester); the collagen maturation index was higher in the Marlex® mesh, followed by Ultrapro®, Parietex Composite® and Vicryl® meshes.

Ceftiofur-loaded PHBV microparticles: a potential formulation for a long-acting antibiotic to treat animal infections

Background: The infectious diseases in the livestock breeding industry represent a significant drawback that generates substantial economic loss and have led to the indiscriminate use of antibiotics. The formulation of polymeric microparticles loaded with antibiotics for veterinary use can: reduce the number of required doses; protect the drug from inactivation; and maintain a sustained-release of the antibiotic drug at effective levels. Accomplishing all of these goals would have a significant economic and animal health impact on the livestock breeding industry. Results: In this work, we formulated ceftiofur-loaded PHBV microparticles (PHBV-CEF) with a spherical shape, a smooth surface and diameter sizes between 1.65 and 2.37 μm. The encapsulation efficiency was 39.5 +/- 1.1 percent w/w, and we obtained a sustained release of ceftiofur in PBS-buffer (pH 7.4) over 7 days. The antibacterial activity of ceftiofur was preserved after the encapsulation procedure, and toxicity of PHBV-CEF microparticles evaluated by MTS was represented by an IC50 > 10 mg/mL. Conclusions: Our results suggest that PHBV-CEF particles have a potential application for improving the treatment of infectious diseases in the livestock breeding industry.

Sistemas biodegradáveis contendo acetato de prednisolona para administração orbitária / Biodegradable systems containing prednisolone acetate for orbital administration

OBJETIVO: O presente estudo objetivou o desenvolvimento e a avaliação de um sistema biodegradável de liberação de fármacos com característica de liberação prolongada, destinado à administração orbitária de acetato de prednisolona (AP). MÉTODOS: O sistema desenvolvido, na forma de microesferas (MEs) de poli-e-caprolactona (PCL) contendo o AP, foi obtido pelo método de evaporação de solvente. As MEs foram caracterizadas por microscopia eletrônica de varredura (MEV), calorimetria diferencial exploratória (DSC), avaliação do teor de encapsulação e pelo perfil de liberação in vitro. O perfil de liberação in vivo foi avaliado em coelhos após administração peribulbar de uma suspensão aquosa das MEs. A biocompatibilidade local do sistema foi verificada por meio de análise histopatológica da região de implantação. RESULTADOS: Após obtenção das MEs, a análise morfológica por MEV mostrou a viabilidade do método de obtenção do sistema. O teor de AP encapsulado foi de 43 ± 7 por cento e pode ser considerado bastante satisfatório. A caracterização do sistema por DSC, além de confirmar a sua estabilidade, não indicou a existência de interação entre o fármaco e o polímero. O estudo de liberação in vitro indicou que o sistema apresenta perfil de liberação prolongada. O estudo in vivo confirmou o perfil de liberação prolongado do AP a partir das MEs, sugerindo, também, a viabilidade do sistema devido à ausência de toxicidade local. CONCLUSÃO: O conjunto dos resultados obtidos neste trabalho é relevante e credencia o sistema desenvolvido como uma possível alternativa ao tratamento de orbitopatias inflamatórias.

PURPOSE: The present study aimed to evaluate an injectable extended-release formulation of prednisolone acetate (PA) for orbital administration. METHODS: Microspheres (MEs) of poly-e-caprolactone (PCL) containing PA were developed by the method of solvent evaporation. The MEs obtained were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), encapsulation efficiency and in vitro release profile. The in vivo release profile was evaluated in rabbits after periocular injection of an aqueous suspension of MEs. The local biocompatibility of the system was verified by histopathologic analysis of the deployment region. RESULTS: After MEs preparation, morphological analysis by SEM showed the feasibility of the employed method. The content of PA encapsulated was 43 ± 7 percent and can be considered as satisfactory. The system characterization by DSC technique, in addition to confirm the system stability, did not indicate the existence of interaction between the drug and the polymer. The in vitro release study showed the prolonged-release features of the developed system. Preliminary in vivo study showed the absence of local toxicity and confirmed the prolonged release profile of PA from MEs, suggesting the viability of the developed system for the treatment of orbital inflammatory diseases. CONCLUSION: The results obtained in this work are relevant and accredit the system developed as a possible alternative to the treatment of inflammatory orbitopathy.