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Nanoemulsions are considered as the most promising solution to improve the delivery of ophthalmic drugs. The design of ophthalmic nanoemulsions requires an extensive understanding of pharmaceutical as well as technological aspects related to the selection of excipients and formulation processes. This Review aims at providing the readers with a comprehensive summary of possible compositions of nanoemulsions, methods for their formulation (both laboratory and industrial), and differences between technological approaches, along with an extensive outline of the research methods enabling the confirmation of in vitro properties, pharmaceutical performance, and biological activity of the obtained product. The composition of the formulation has a major influence on the properties of the final product obtained with low-energy emulsification methods. Increasing interest in high-energy emulsification methods is a consequence of their scalability important from the industrial perspective. Considering the high-energy emulsification methods, both the composition and conditions of the process (e.g., device power level, pressure, temperature, homogenization time, or number of cycles) are important for the properties and stability of nanoemulsions. It is advisible to determine the effect of each parameter on the quality of the product to establish the optimal process parameters’ range which, in turn, results in a more reproducible and efficient production.

Despite extensive use of micelles in materials and colloidal science, their supramolecular organization as well as host-guest interactions within these dynamic assemblies are poorly understood. Small guest molecules in the presence of micelles undergo constant exchange between a micellar aggregate and the surrounding solution, posing a considerable challenge for their molecular level characterisation. In this work we reveal the interaction maps between small guest molecules and surfactants forming micelles via novel applications of NMR techniques supported with state-of-the-art analytical methods used in colloidal science. Model micelles composed of structurally distinct surfactants (block non-ionic polymer Pluronic® F-127, non-ionic surfactant Tween 20 or Tween 80 and ionic surfactant SLS, sodium lauryl sulphate) were selected and loaded with model small molecules of biochemical relevance (i.e. the drugs fluconazole, FLU or indomethacin, IMC) known to have different partition coefficients. Molecular level organization of FLU or IMC within hydrophilic and hydrophobic domains of micellar aggregates was established using combination of NMR methods (1D 1H NMR, 1D 19F NMR, 2D 1H-1H NOESY and 2D 1H-19F HOESY, and the multifrequency-STD NMR) and corroborated with molecular dynamics (MD) simulations. This is the first application of multifrequency-STD NMR to colloidal systems, enabling us to elucidate intricately detailed patterns of drug/micelle interactions in a single NMR experiment within minutes. Importantly, our results indicate that flexible surfactants, such as block copolymers and polysorbates, form micellar aggregates with a surface composed of both hydrophilic and hydrophobic domains and do not follow the classical core-shell model of the micelle. We propose that the magnitude of the changes in 1H chemical shifts corroborated with interaction maps obtained from DEEP-STD NMR and 2D NMR experiments can be used as an indicator of the strength of the guest-surfactant interactions. This NMR toolbox can be adopted for the analysis of broad range colloidal host-guest systems from soft materials to biological systems.

Increasing access to additive manufacturing technologies utilising easily available desktop devices opened novel ways for formulation of personalized medicines. It is, however, challenging to propose a flexible and robust formulation platform which can be used for fabrication of tailored solid dosage forms composed of APIs with different properties (e.g., hydrophobicity) without extensive optimization. This manuscript presents a strategy for formulation of fast dissolving tablets using binder jetting (BJ) technology. The approach is demonstrated using two model APIs: hydrophilic quinapril hydrochloride (QHCl, logP = 1.4) and hydrophobic clotrimazole (CLO, logP = 5.4). The proposed printing method uses inexpensive well known and easily available FDA approved pharmaceutical excipients. The obtained model tablets had uniform content of the drug, excellent mechanical properties and highly porous structure resulting in short disintegration time and fast dissolution rate. The tablets could be scaled and obtained in predesigned shapes and sizes. The proposed method may find its application in the early stages of drug development where high flexibility of the formulation is required and the amount of available API is limited.

OBJECTIVE Otitis media is one of the most common illnesses which may cause ossicles destruction and conductive hearing loss. However, nowadays the damaged middle ear bones may be replaced by a partial or total ossicular replacement prosthesis. The main aim of this article was to confirm the proper functioning of the new middle ear prosthesis. METHODS This work describes first clinical trials conducted on a group of three patients with the case of interrupted ossicles continuity and chronic otitis media. The clinical trials were performed according to permission No. 157/KBL/OIL2016. The patients were subjected to the bones chain reconstruction via implanting a bactericidal middle ear prosthesis called Otoimplant. The following preoperative and postoperative parameters have been evaluated: Air-Bone-Gap values, mean ABG values in different frequencies, bone and air conductivity, speech audiometry and microbiological assessment. The patients' recovery was observed according to the study protocol on the 7th day and 1, 3, 6 and 12 months after the surgery. RESULTS Audiological tests revealed that the mean Air-Bone-Gap was reduced by 36% in all the patients after 1 year. No bacteria or fungi were found in the middle ear spaces. CONCLUSIONS Results confirm the bactericidal efficacy and hearing improvement of the Otoimplant.

Relations between structural modifiactions and SOD-like activity of four branched CuII-metallopeptides based on l-2,3-diaminopropionic acid are reported. The IC50 values (McCord–Fridovich method) illustrate that enhanced SOD-like activity is warranted by exclusive N-terminal His localization that surmounts the driving force by the CuII/I formal potential.

Background: Oral Lichen planus (OLP) is a chronic inflammatory disease. Topical steroids are used as the treatment of choice. The alternative is photodynamic therapy (PDT). The study aimed to fabricate optimal biodegradable matrices for methylene blue or triamcinolone acetonide because of a lack of currently commercially available carriers that could adhere to the mucous. Methods: The study was designed as a 12-week single-blind prospective randomized clinical trial with 30 patients, full contralateral split-mouth design. Matrices for steroid and photosensitizer and laser device were fabricated. Fractal and texture analysis of photographs, taken in 405, 450, 405 + 450 nm wavelength, of lesions was performed to increase the objectivity of the assessment of treatment. Results: We achieved two total responses for treatment in case of steroid therapy and one in the case of PDT. Partial response was noted in 17 lesions treated using local steroid therapy and 21 in the case of PDT. No statistically significant differences were found between the effectiveness of both used methods. Statistically significant differences in fractal dimension before and after treatment were observed only in the analysis of photographs taken in 405 + 450 nm wavelength. Conclusions: Photodynamic therapy and topical steroid therapy are effective methods for treating OLP. Using a carrier offers the possibility of a more predictable and effective method of drug delivery into the mucous membrane. Autofluorescence enables the detection of lesions especially at the early stage of their development.

The imidazole ring of histidine (His) and the methylcarboxylate function of aspartic acid (Asp) are crucial for Cu coordination in enzymes, artificial proteins and other bioinspired systems. In order to elucidate the effect of Asp at the C-terminus, a new branched peptide, H-Gly-Dap(H-Gly)-Asp-NH2 (2GD, Dap = 2,3-diaminopropionic acid) has been synthesized to ligate CuII. While at pH < 8, 2GD favours dimeric complexes at 1 : 1 metal-to-ligand ratio, at increasingly alkaline pH the Asp at the C-terminus creates a {NH2,N−,N−,O−}eq set and the dominance of mononuclear CuLH−2 and CuLH−3 species, according to potentiometry, molecular spectroscopy (UV-visible, circular dichroism and X-band electron paramagnetic resonance) and ESI-MS analysis. The changes in speciation with pH are accompanied by shifts in the CuIII/II redox current peaks that were analyzed by square wave voltammetry (SWV) and allowed the calculation of the pKa values for the CuII and CuIII forms. The 2GD complex exhibits electrocatalytic activity in water oxidation in phosphate buffer. However, when Asp residues are present at all three termini to produce 3D (H-Asp-Dap(H-Asp)-Asp-NH2), the electrocatalysis of water oxidation decreases and, if present only at the N-termini in 2DG (H-Asp-Dap(H-Asp)-Gly-NH2), it ceases. As for CuII ligated by 2GD, a TOF of ∼16 s−1 was calculated at pH = 11 in 0.2 M phosphate electrolyte, which is crucial for catalysis, but also acts as inhibitor anion according to cyclic voltammetry observations. The system is highly tolerant to the presence of chloride, which is a feature of practical importance in efficient water oxidation catalysis.

Paragangliomas of the head and neck region are rare and predominantly asymptomatic tumors. These neoplasms arise from widely distributed paraganglionic cells, which originate from both mesodermal elements of third branchial arch and the neural crest residues. Despite the rare occurrence of paragangliomas, problems encountered in their diagnosis, unclear malignancy and treatment ensure that they still remain in the focus of head and neck surgeons. This is a retrospective study of the medical records of patients treated in the ENT Department of the 5th Military Hospital in Krakow during the period 2010-2014. All the preoperative, intraoperative and postoperative data were carefully analyzed for each patient. Thirteen patients (16 tumors) were treated during the study period. All the patients with a pre-operative suspicion of paraganglioma underwent computed tomography angiography. The whole cohort of patients was treated surgically. Paraganglioma should be always considered in the differential diagnosis for painless neck masses. These tumors require thorough radiological pre-operative evaluation and skilled operative technique. Surgical treatment occurs to provide good cure rates with minimal recurrence and morbidity rates.

1 Skin reactions are the most common complications after BAHA implantation. 2 The excess of soft tissue leads to inability to tack the hearing ad to the abutment which prevents the effective use of sound processor. 3 This is a prospective case series of 8 patients with skin overgrowth around the BAHA abutments treated with CO2 laser. 4 This case-series suggest that CO2 laser is safe and easy method for the treatment of the skin overgrowth around the BAHA abutment. 5 This is the first case series presentation of the CO2 laser surgery for treatment of the skin overgrowth around the abutment of BAHA This article is protected by copyright. All rights reserved.

Introduction: The Focal Infection Theory, originally presented at the beginning of the 20 th century, postulates that systemic diseases can be caused by microorganisms that arise from the focus of infection. Foci of infections have been described as sinuses, adenoids, tonsils, teeth, genitourinary tract, gall bladder and kidneys. A focus of infec - tion is defined as the area that can occur in any part of the body, contains a pathogen (microorganism) and is usu - ally asymptomatic. There are discordant opinions about the role of focal infections in the pathogenesis of psoria - sis and urticaria. Aim: To establish whether there is a higher incidence of focal infections in patients with chronic urticaria and pso - riasis. Material and methods: We retrospectively reviewed 129 patients with a history of psoriasis and chronic urticaria: 58 women and 71 men treated in the Department of Dermatology of the Jagiellonian University Medical College in Krakow. Results:In the analyzed group, 11 patients had a dental consultation, 58 - laryngological consultation and 29 women had a gynecological consultation. The most common examples of focal infection were tonsillitis, upper respiratory tract infections, sinusitis, dental caries and genitourinary tract infections. Aggravating factors were similar to pre - viously described. Conclusions: A high incidence of focal infections in patients with psoriasis and urticaria suggests that infections may play a significant role in the pathogenesis of these skin disorders. Treatment of infection foci may play the key role in the remission of skin changes.

Introduction Antiphospholipid syndrome (APS) is a common acquired thrombophilia associated with a high thrombotic risk, in which vitamin K antagonists (VKA) represent the mainstay of therapy. Case series involving up to 35 patients with APS suggested limited efficacy and safety of direct oral anticoagulants (DOACs). Material and methods In the prospective case series we followed 56 consecutive patients with APS (44 women and 12 men, aged from 22 to 64 years), including 33 (60%) associated with systemic lupus erythematosus (SLE) and 16 (28.6%) with triple APS who were treated with DOACs due to their preferences or unstable anticoagulation with VKA. DOACs were started at least 3 months since the thromboembolic event in patients with D-dimer below 500 ng/ml. Results Forty-nine (87.5%) patients were treated with rivaroxaban, 4 (7.3%) with dabigatran and 3 (5.4%) with apixaban. During follow-up of 2 to 43 (mean 22) months, 6 (10.7%, 5.8 per 100 patient-years) patients (4 women and 2 men, 4 with triple positive APS) experienced recurrent thrombosis, including deep vein thrombosis (n = 4, including 2 episodes preceded by nonadherence), superficial vein thrombosis (n = 1) and non-ST elevation myocardial infarction (n = 1). The recurrence rate of VTE on DOACs was 5.8 per 100 patient-years. Two patients (3.6%) experienced severe bleeding. Conclusions This case-series suggests that DOACs are safe in patients with APS. These findings need to be confirmed in larger studies.

The aim of current bone biomaterials research is to design implants that induce controlled, guided, successful, and rapid healing. Titanium implants are widely used in dental, orthopedic, and reconstructive surgery. A series of studies has indicated that cells can respond not only to the chemical properties of the biomaterial, but also, in particular, to the changes in surface topography. Nanoporous materials remain in focus of scientific queries due to their exclusive properties and broad applications. One such material is nanostructured titanium oxide with highly ordered, mutually perpendicular nanopores. Nanoporous anodic titanium dioxide (TiO2) films were fabricated by a three-step anodization process in propan-1,2,3-triol-based electrolyte containing fluoride ions. Adipose-derived stem cells offer many interesting opportunities for regenerative medicine. The important goal of tissue engineering is to direct stem cell differentiation into a desired cell lineage. The influence of nanoporous TiO2 with pore diameters of 80 and 108 nm on cell response, growth, viability, and ability to differentiate into osteoblastic lineage of human adipose-derived progenitors was explored. Cells were harvested from the subcutaneous abdominal fat tissue by a simple, minimally invasive, and inexpensive method. Our results indicate that anodic nanostructured TiO2 is a safe and nontoxic biomaterial. In vitro studies demonstrated that the nanotopography induced and enhanced osteodifferentiation of human adipose-derived stem cells from the abdominal subcutaneous fat tissue.

Basal cell carcinoma (BCC) is the most common malignancy in humans [1, 2]. According to the Skin Cancer Foundation, estimated 2.8 million cases are diagnosed annually in the US. Non-melanoma skin cancers (NMSC), the most common neoplasms in Europe, the USA and Australia, despite their low mortality, pose a serious therapeutic, social and economic problem. Worldwide incidence is increasing by about 10% per annum, so the prevalence of basal cell tumor in the near future will equal that of all other cancers together [3]. Basal cell carcinoma occurs in 85–90% of cases on the head, often on the face above the line connecting the mouth corner with the ear lobe [4]. They are less often found in the lower part of the face and on the scalp. In 10–15% of cases, BCC is found on the neck, trunk and limbs. Location of the basal cell carcinoma is closely related to the exposure to ultraviolet radiation [5, 6]. Although rarely metastatic, it has potential of tremendous, in some locations, life-threating, regional destruction and disfigurement [7]. Diseases on the surface of the skin are usually visible and tend to be easily noticed both for health-care professionals and for patients themselves. However, cases of neglected, extensive skin neoplasms are still a fairly common phenomenon in the 21st century. There are several different methods of treatment of BCC tumors: surgical (simple excision, Mosh’ micrographic surgery), destructive (cryosurgery, curettage and cautery) and non-surgical (photodynamic therapy, radiotherapy, topical-5-fluorouracil, imiquimod) [8, 9]. An advantage of surgical proceeding is the possibility of meticulous histological examination of the tumor type and margins of excision to establish clearance. Early treatment produces cure rates of almost 100% (the suggested overall 5-year cure rates for primary and recurrent BCC are 99% and 94.4%, respectively) [10, 11]. In order to decide on the adequate treatment option, several factors should be taken into consideration: biological, histopathological and clinical features of the neoplasm as well as the patient condition. Exact determination of the skin cancer margins is of particular importance in case of lesions developing in areas where the reoperation of a recurring neoplasm would not be possible. When excision is incomplete, the recurrence rate is approximately 30% [12]. Basal cell tumors are easily treated in their early stages. The larger the tumor has grown, however, the more extensive the treatment is needed. Especially some locations (eyelids, nose flap, lips, auricle) pose a challenge for the surgeon to remove the tumor entirely with proper margins and at the same time retain functionality and satisfactory aesthetic appearance. Furthermore, large, neglected tumor, especially located in the face region, demands complex reconstructive procedures after excision, i.e. local reconstruction techniques, free grafts, advanced, island, pedicle or microvascular flaps. A male patient, aged 66, was admitted to the Department of Otolaryngology of the 5th Military Hospital in Krakow due to large, progressive neoplastic ulceration of the right side of his face. He reported 9-year history of a slowly but gradually growing ulcerating lesion of the right buccal region. Three months before admission, he started to suffer from stabbing pain in the lower part of his face, leaking of saliva and bites of food through the ulceration, disturbances in nutrition, and unintentional, significant weight loss (approximately 15 kg in the past 12 months). The patient was in good general condition (concomitant diseases were benign prostate hypertrophy, left inguinal hernia treated surgically in 1994), evaluated as Fitzpatrick's skin photo type II, abusing nicotine. Physical examination revealed extensive, full-thickness ulceration of the right buccal region extending upward to the zygomatic arch, with destruction of the half of the upper lip and one third of the lower lip, infiltrating surrounding mimic muscles, exposing the bone of the body of the mandible, invading the mucosa of the alveolar rim of the mandible (Figures 1 and ​and2)2) [1, 2]. Figure 1 Large, neglected basal cell carcinoma of the right facial region Figure 2 Large, neglected basal cell carcinoma of the facial region In the histological samples taken from the ulceration basal cell carcinoma with perineural infiltration was revealed, but the planoepithelial component could not be excluded. The computed tomography (CT) scans revealed an extensive tissue loss and the possibility of infiltration of the mandible in the region of the right mental foramen. The patient was qualified to the surgical treatment (Figures 3 and ​and44). Figure 3 Harvesting of the musculocutaneous anterolateral thigh flap Figure 4 Microvascular anastomosis with facial vessels The first part of the procedure consisted of resection of the tumor within the histologically clean margins-right buccal region, 1/2 of the upper lip, 1/3 of the lower lip, segmental resection of the right body of the mandible, dental extraction (teeth: 41–45, 12–14) and elective right neck dissection of lymph nodes I–V and submandibular gland (RND (I–V + SG)). The non-lymphatic structures were spared (with special concern for internal jugular vein and facial vessels). The post resection mandible loss was bridged with titanium miniplate. The abundant soft tissue defect was reconstructed with a combination of autologous split-thickness skin graft from the left thigh and microvascular musculocutaneous (based on vastus lateralis muscle) free flap antero-lateral part of the right thigh [3]. Vascular pedicle (6 cm long) consisted of one artery and two veins (diameter approximately 2 cm). The microvascular end-to-end anastomosis was made to the right facial vessels [5]. Evaluation of the patency of the anastomosis was made – the blood flow was satisfactory. In the postoperative care, the patient was monitored every 4 h (general condition, flap color, warmth, pin prick) administered with the analgesics, wide-spectrum antibiotics, low-molecular-weight heparin, nourished by the nasogastric tube. In the eleventh [6] week of the post-operative period he underwent a minor procedure under local anesthesia of the reconstruction of the mouth (Figures 5 and ​and6)6) [7]. Figure 5 Eleven weeks after surgery Figure 6 Reconstruction of the mouth Fifteen weeks after surgery he did not complain of pain, he gained weight of approximately 8 kg, the esthetic outcome was satisfactory. Skin tumors are generally visible and noticeable not only for health care workers but also for the patients themselves. However typical BCCs are indolent and slowly progressive. These tumors remain painless and unobtrusive for long time. In addition, for non-specialists in skin diseases, BCC sometimes resembles noncancerous skin conditions such as psoriasis, eczema or others. The natural history of this cancer makes it an “ideal candidate” for neglected tumor. An extremely important issue in the treatment of locally advanced tumors is the choice of the appropriate method of treatment. Numerous alternatives are available for small BCC lesions: surgical excision, Mosh micrographic surgery, photodynamic therapy, cryosurgery, immunotherapy, and radiotherapy are the most common techniques. The treatment of expansive, neglected tumors, however, often demands a multidisciplinary approach. The treatment of choice for advanced cancers is usually surgery (also neurosurgery, cranio-maxillo-facial surgery, plastic surgery) sometimes combined with radiation therapy. The key point is also the choice of the most beneficial type of reconstructive treatment after ablation of the tumor. The goal is to restore the functionality and esthetically satisfactory appearance, especially after surgery of the tumors of the head and neck with possibly small sacrifice of other tissues [13]. One of attractive reconstructive methods for large defects are free microvascular flaps. Microsurgery has evolved to focus on functional and aesthetic results, as well as donor site morbidity. The qualities of an ideal soft tissue flap for reconstructions in the head and neck region are versatility in design, adequate tissue stock, specific texture, long pedicle with an appropriate diameter of vessels, possibility of two team approach, consistent anatomy, easy and safe dissection and minimal donor site morbidity. One of the alternatives is the anterolateral thigh flap (ALTF). It could be elevated as a cutaneous or musculocutaneous flap (based on vastus lateralis muscle) [14]. It has relatively constant anatomy, which makes dissection safe and easy for a skilled surgeon. Large and long pedicle, with a diameter close to potential recipient vessels of the head and neck make the microvascular anastomosis safe and easy. Harvesting ALTF is related with minimal donor site morbidity. The motor weakness is mild and transient, and the donor site can be closed primarily if the width of the skin island of the flap is less than 8 cm [15, 16]. Although the anterolateral thigh flap has become the workhorse for reconstruction of the skin and soft tissue defects since Song et al. first described it in 1984, are still used very rarely. The basal skin carcinoma, although considered to be the tumor with the low malignancy potential and not significant clinical problem, neglected advanced tumors can be encountered even in the 21th century. There is an entire range of possibilities for the treatment of basal cell lesions, but the therapy of such neglected cases usually demands multidisciplinary surgical and oncological treatment with advanced reconstructive techniques.

Gunshot injuries of the viscerocranium are rarely reported during times of peace in Europe. Penetrating wounds to the maxillofacial region pose a significant challenge for surgeons as they often comprise serious soft and bone tissue defects.We present a case report of 38-year-old male with gunshot wound to the viscerocranium after suicidal attempt. The patient's general condition was stable. The inlet wound was found in the submental region in the central line penetrating deep into the floor of the mouth, to the left, avoiding large vessels and hypoglossal nerve. No exit wound was identified. The ophthalmic examination revealed the limitation of motion in the left eyeball and diplopia in the whole field of vision. The revision was performed under general anesthesia. Control CT scan revealed the presence of one metallic fragment wedged in the hard palate. Second look of oral cavity with particular emphasis on the hard palate was performed. Shrapnel proved to be wedged in the bone of the hard palate very firmly and complete removal without damaging the function of the palate was impossible. The decision was made to withdraw from surgical removal of the remaining piece of the projectile. In most cases, it is recommended to remove all foreign material from human body. However, in the illustrated case we decided to leave small debris in the craniofacial skeleton. In our opinion, further surgical revision would result in greater tissue damage, disproportionate to the benefits of the removal of all fragments of the projectile.

Katarzyna Malec,1 Joanna Góralska,1 Magdalena Hubalewska-Mazgaj,2 Paulina Glowacz,1 Magdalena Jarosz,3 Pawel Brzewski,4 Grzegorz D Sulka,3 Marian Jaskula,3 Iwona Wybranska1 1Department of Clinical Biochemistry, Jagiellonian University Medical College, 2Department of Genetic Research and Nutrigenomics, Malopolska Centre of Biotechnology, Jagiellonian University, 3Department of Physical Chemistry and Electrochemistry, Faculty of Chemistry, Jagiellonian University, 4Department of Dermatology, Jagiellonian University Medical College, Kraków, Poland Abstract: The aim of current bone biomaterials research is to design implants that induce controlled, guided, successful, and rapid healing. Titanium implants are widely used in dental, orthopedic, and reconstructive surgery. A series of studies has indicated that cells can respond not only to the chemical properties of the biomaterial, but also, in particular, to the changes in surface topography. Nanoporous materials remain in focus of scientific queries due to their exclusive properties and broad applications. One such material is nanostructured titanium oxide with highly ordered, mutually perpendicular nanopores. Nanoporous anodic titanium dioxide (TiO2) films were fabricated by a three-step anodization process in propan-1,2,3-triol-based electrolyte containing fluoride ions. Adipose-derived stem cells offer many interesting opportunities for regenerative medicine. The important goal of tissue engineering is to direct stem cell differentiation into a desired cell lineage. The influence of nanoporous TiO2 with pore diameters of 80 and 108 nm on cell response, growth, viability, and ability to differentiate into osteoblastic lineage of human adipose-derived progenitors was explored. Cells were harvested from the subcutaneous abdominal fat tissue by a simple, minimally invasive, and inexpensive method. Our results indicate that anodic nanostructured TiO2 is a safe and nontoxic biomaterial. In vitro studies demonstrated that the nanotopography induced and enhanced osteodifferentiation of human adipose-derived stem cells from the abdominal subcutaneous fat tissue. Keywords: adipose-derived stem cells, anodic titanium oxide, nanotopography, osteogenic differentiation, biomaterials