Fabrication and Modelling of a Reservoir-Based Drug Delivery System for Customizable Release.

Localized therapy approaches have emerged as an alternative drug administration route to overcome the limitations of systemic therapies, such as the crossing of the blood-brain barrier in the case of brain tumor treatment. For this, implantable drug delivery systems (DDS) have been developed and extensively researched. However, to achieve an effective localized treatment, the release kinetics of DDS needs to be controlled in a defined manner, so that the concentration at the tumor site is within the therapeutic window. Thus, a DDS, with patient-specific release kinetics, is crucial for the improvement of therapy. Here, we present a computationally supported reservoir-based DDS (rDDS) development towards patient-specific release kinetics. The rDDS consists of a reservoir surrounded by a polydimethylsiloxane (PDMS) microchannel membrane. By tailoring the rDDS, in terms of membrane porosity, geometry, and drug concentration, the release profiles can be precisely adapted, with respect to the maximum concentration, release rate, and release time. The release is investigated using a model dye for varying parameters, leading to different distinct release profiles, with a maximum release of up to 60 days. Finally, a computational simulation, considering exemplary in vivo conditions (e.g., exchange of cerebrospinal fluid), is used to study the resulting drug release profiles, demonstrating the customizability of the system. The establishment of a computationally supported workflow, for development towards a patient-specific rDDS, in combination with the transfer to suitable drugs, could significantly improve the efficacy of localized therapy approaches.

Accurate and cost-effective mandibular biomodels: a standardized evaluation of 3D-Printing via fused layer deposition modeling on soluble support structures.

INTRODUCTION: Medical biomodels can be used for illustration of medical conditions, preoperative planning or to facilitate pre-bending of osteosynthesis material. They have been shown to be an effective and efficient method to reduce operating time, blood loss and wound stress in cranio-maxillo-facial surgery. Lately, new time and cost-efficient 3D-printing methods have been introduced into the mass-market. The aim of this study was to establish a standardized method of evaluation and consequently evaluate Fused Layer Deposition Modeling in combination with soluble support structures for fabrication of medical biomodels regarding precision and cost-effectiveness. MATERIALS & METHODS: Twenty-one biomodels of human mandibles equipped with measuring appliances were printed on a FLDM 3D-printers (Ultimaker 3 Extended) using a polyactate filament and a water-soluble Polyvinyl alcohol-based support structures. Precision of these models was compared to commercial, polyamide sintered models and the planning data. Production costs, printing times and post processing procedures were evaluated. RESULTS: Duration of printing of mandibular biomodels was between 6 h 5 min - 15 h 9 min (mean 9 h 12 min, ±2 h 25 min). The average cost of materials was €5.90 (± €1.28) per model. With an average aberrance of 0.29 mm, FLDM printing delivered a high level of accuracy. It was significantly superior to the polyamide reference models in the area of the semilunar incision, yet inferior at the coronoid process. CONCLUSION: FLDM printers are able to provide very precise biomodels at very low costs. The use of using soluble support structures reduces time, costs and equipment needed for post processing procedures close to zero.

Patient-specific implant modification for alloplastic bridging of mandibular segmental defects in head and neck surgery.

Displacement of the remaining mandibular segments may occur after alloplastic bridging of mandibular segmental defects using patient-specific reconstruction plates. Consequently, additional surgical devices are required for correct plate positioning. Patient-specific reconstruction plates with a conventional one beam-like design (cPSRP) have been modified by adding two flanges and giving a Y-shape to the distal ascending implant part to allow for segment positioning without using additional devices. We aimed to evaluate reconstruction results after using these modified patient-specific reconstruction plates (mPSRP). We compared the reconstruction results for mPSRP and cPSRP and evaluated mandibular segment dislocations after reconstruction using digital image analysis of the pre- and postoperative radiological data sets. Analysis showed better reconstruction results with mPSRP than with cPSRP; mean dislocation values concerning shifts and rotations of mandibular segments were lower for mPSRP (x-axis: 2.9 mm vs 1.1 mm, 4.2° vs 3.6°; y-axis: 6.0 mm vs 2.0 mm, 3.5° vs 2.8°; z-axis: 3.9 mm vs 3.3 mm, 4.2° vs 1.2°). Significant differences were found for shifts along the y-axis (p = 0.039) and rotations around the z-axis (p = 0.041). Therefore, implant design modifications with additional positioning elements could help simplify surgical reconstruction procedures and improve reconstruction in head and neck surgery.

Angiogenic effects of mesenchymal stem cells in combination with different scaffold materials.

Tissue survival in regenerative tissue engineering requires rapid vascularization, which is influenced by scaffold material and seeded cell selection. Poly-l-lactide-co-glycolide (PLGA) and beta-tricalcium phosphate (ß-TCP) are well-established biomaterials with angiogenic effects because of their material properties. Given the importance of the seeded cell type as a co-factor for vascularization, mesenchymal stem cells (MSCs) are known to have high angiogenic potential. We hypothesized that PLGA and ß-TCP scaffolds seeded with MSCs would effectively induce a potent angiogenic response. Therefore, we studied the angiogenic effects after implanting PLGA and ß-TCP scaffolds seeded with isogeneic MSCs in vivo. Fifty-six BALB/c mice were equally divided into seven groups and underwent implantation of the dorsal skinfold chambers. Two MSC groups were seeded on collagen-coated PLGA or ß-TCP scaffolds, whereas groups 3-6 received collagen-coated or uncoated scaffolds without MSCs. No scaffold implantation was performed for group 7, which served as the control. Angiogenesis was assessed in vivo via intravital fluorescence microscopy. Angiogenic responses were noted on all scaffolds, whereupon MSC angiogenic response was significantly enhanced on days 6 and 10. Additionally, a comparison of biomaterials indicated increased angiogenic activity for ß-TCP scaffolds compared with PLGA scaffolds. In conclusion, seeding ß-TCP scaffolds with MSCs can accelerate vitalization and a combination of both significantly improves angiogenesis.

Current Strategies in Post-traumatic Orbital Reconstruction.

Posttraumatic orbital reconstruction is one of the most fascinating fields in reconstructive craniomaxillofacial surgery. Hardly any other field in craniomaxillofacial surgery has changed so much in terms of diagnostics, biomaterial selection for reconstruction, surgical techniques including approaches and quality control. In particular, in the field of reconstructive orbital surgery all advances in modern medical treatment are summarized and represented. Reconstructive orbital surgery thus became the medical field spearheading all reconstructive surgical specialties in terms of use of DICOM-data, computer assistance, change towards patient-specific solutions and establishing digital workflows for adequate quality control during all phases of treatment, i.e. pre-, intra- and postoperative. With this paper, this evolutionary process shall be demonstrated as well as display the spirit of change that was necessary to optimize reconstructive orbital surgery and to improve medical care in all areas of reconstruction. Finally, reconstructive orbital surgery could prove to be a highly foreseeable field nowadays, thus giving the next generation of CMF-surgeons a huge opportunity to drive this topic further into the future.

Survival Rates According to Tumour Location in Patients With Surgically Treated Oral and Oropharyngeal Squamous Cell Carcinoma.

BACKGROUND/AIM: We evaluated survival rates in surgically-treated oral and oropharyngeal squamous cell carcinoma patients at our clinic, and determined whether survival differed by tumour locations. PATIENTS AND METHODS: In a retrospective study, tumour lesions in 1,486 patients were categorized into 6 groups according to tumour location. Patients' age, sex, tumour-node-metastasis classification, resection status, 5-year and disease-specific survival rates were statistically analysed between groups. RESULTS: A significantly inferior disease-specific and lower 5-year survival rates for tumours located at the base of the tongue and oropharynx, and maxilla, due to higher T-stage and incomplete resection status were shown. Cervical lymph node metastasis and distant metastatic spread were more frequently observed with base of the tongue and oropharynx lesions. CONCLUSION: Attentive inspection and precise clinical examinations of specific oral and oropharyngeal regions are crucial for early diagnosis and treatment. Oral and oropharyngeal tumour locations play important roles in disease prognosis.

Physical and Psychological Impairments Associated with Mucositis after Oral Cancer Treatment and Their Impact on Quality of Life.

BACKGROUND: Posttherapeutic mucositis is a common secondary effect of oral cancer treatment. Mucositis affects the oral mucosa, which leads to specific physical impairments in oral function and a negative impact on quality of life. OBJECTIVE: To evaluate the impairments associated with oral mucositis and their impact on posttherapeutic quality of life. METHODS: A retrospective analysis was conducted on 1,652 patients treated for oral cancer during the multicenter rehabilitation study of the German-Austrian-Swiss Cooperative Group on Tumors of the Maxillofacial Region (DÖSAK), which included 43 clinics from Germany, Austria, and Switzerland. The analysis was based on questionnaires filled out by patients following treatment. RESULTS: Approximately 10% of 1,652 patients included in our study had physical or psychological impairments due to increased posttreatment oral mucositis; this was mainly due to adjuvant radiotherapy or radiochemotherapy administered. Oral mucositis was significantly associated with specific physical impairments, especially xerostomia and pain (p = 0.000), which required supportive care and analgesia (p = 0.000). Additionally, impaired ingestion and speech significantly led to psychological disorders such as public avoidance behavior and social isolation (p = 0.001). Depressive coping of disease (p = 0.001) and concomitant depressive tendencies (p = 0.004) were highly associated with mucositis, which was accompanied by diminished general condition (p = 0.001), bleak future prospects (p = 0.006), and a reduction in quality of life (p = 0.002). CONCLUSION: Minimizing mucositis-related impairments should be a main effort in oral cancer treatment to optimize patient outcome and improve quality of life after therapy.

Ossification of the Vascular Pedicle After Microsurgical Soft Tissue Transfer of the Lateral Upper Arm Free Flap.

Reconstruction of intraoral defects is one of the main aspects of head and neck cancer treatment. Since the advent of microvascular surgery in this field, free flap tissue transfer has become a common procedure, and various flaps have been described for soft tissue reconstruction. The lateral upper arm free flap is one of the most frequently used flaps for intraoral defect coverage. This article describes ossification of the corresponding vascular pedicle after soft tissue transfer with the lateral upper arm free flap and microsurgical anastomosis in oral cancer treatment. Similar findings in the context of the lateral upper arm free flap have never been reported in the literature; however, it is important for surgeons to know that pedicle ossification can occur. This knowledge may be helpful to avoid erroneous diagnosis of the ossification as a sign of tumor relapse/recurrence as well as to anticipate potential difficulties in the surgical approach in cases requiring reentry of the reconstructed region, for example, in relapse/recurrence of head and neck cancer.

Heterotopic bone formation in the musculus latissimus dorsi of sheep using ß-tricalcium phosphate scaffolds: evaluation of different seeding techniques.

Osseous reconstruction of large bone defects remains a challenge in oral and maxillofacial surgery. In addition to autogenous bone grafts, which despite potential donor-site mobility still represent the gold standard in reconstructive surgery, many studies have investigated less invasive alternatives such as in vitro cultivation techniques. This study compared different types of seeding techniques on pure ß-tricalcium phosphate scaffolds in terms of bone formation and ceramic resorption in vivo. Cylindrical scaffolds loaded with autologous cancellous bone, venous blood, bone marrow aspirate concentrate or extracorporeal in vitro cultivated bone marrow stromal cells were cultured in sheep on a perforator vessel of the musculus latissimus dorsi over a 6-month period. Histological and histomorphometric analyses revealed that scaffolds loaded with cancellous bone were superior at promoting heterotopic bone formation and ceramic degradation, with autogenous bone and bone marrow aspirate concentrate inducing in vivo formation of vital bone tissue. These results confirm that autologous bone constitutes the preferred source of osteoinductive and osteogenic material that can reliably induce heterotopic bone formation in vivo.

A prospective multicenter study to compare the precision of posttraumatic internal orbital reconstruction with standard preformed and individualized orbital implants.

PURPOSE: A variety of implants are available for orbital reconstruction. Titanium orbital mesh plates are available either as standard preformed implants or able to be individualized for the patient. The aim of this study was to analyze whether individualized orbital implants allow a more precise reconstruction of the orbit than standard preformed implants. MATERIALS AND METHODS: A total of 195 patients treated between 2010 and 2014 were followed up to 12 weeks after surgery. Of the patients, 100 had received standardized preformed and 95 individualized implants. The precision of orbital reconstruction with the different implants was determined by comparing the variances in the volume difference between the reconstructed and the contralateral orbit on the postoperative computed tomographic scans. Clinical volume-related parameters including globe position, vision, motility, and diplopia and surgical details including approach, timing and technique of implant modification, use of navigation, duration of surgery, as well as adverse events were documented. RESULTS: Orbital reconstruction was significantly more precise when individualized implants were used. The same was seen with intraoperative navigation. An overlap in the use of individualized implants and navigation makes it difficult to attribute the improved precision to a single factor. CONCLUSION: This study demonstrated that individualization and navigation provide clinical benefit.

Influenza A virus strains differ in sensitivity to the antiviral action of Mx-GTPase.

Interferon-mediated host responses are of great importance for controlling influenza A virus infections. It is well established that the interferon-induced Mx proteins possess powerful antiviral activities toward most influenza viruses. Here we analyzed a range of influenza A virus strains for their sensitivities to murine Mx1 and human MxA proteins and found remarkable differences. Virus strains of avian origin were highly sensitive to Mx1, whereas strains of human origin showed much weaker responses. Artificial reassortments of the viral components in a minireplicon system identified the viral nucleoprotein as the main target structure of Mx1. Interestingly, the recently reconstructed 1918 H1N1 "Spanish flu" virus was much less sensitive than the highly pathogenic avian H5N1 strain A/Vietnam/1203/04 when tested in a minireplicon system. Importantly, the human 1918 virus-based minireplicon system was almost insensitive to inhibition by human MxA, whereas the avian influenza A virus H5N1-derived system was well controlled by MxA. These findings suggest that Mx proteins provide a formidable hurdle that hinders influenza A viruses of avian origin from crossing the species barrier to humans. They further imply that the observed insensitivity of the 1918 virus-based replicon to the antiviral activity of human MxA is a hitherto unrecognized characteristic of the "Spanish flu" virus that may contribute to the high virulence of this unusual pandemic strain.

The antiviral potential of interferon-induced cotton rat Mx proteins against orthomyxovirus (influenza), rhabdovirus, and bunyavirus.

Influenza A virus (FLUAV) is an important human pathogen able to cause devastating pandemics. Recently, cotton rats have been proposed as an animal model to study the innate immune response against FLUAV and other human pathogens. The interferon (IFN)-induced Mx GTPases are part of the cell-autonomous innate immune response against viruses. We, therefore, tested the antiviral activity of the two cotton rat Mx proteins that were recently identified. The nuclear cotton rat Mx1 protein was found to be a strong inhibitor of FLUAV, whereas the cytoplasmic cotton rat Mx2 protein was inactive. Cotton rat Mx2, but not cotton rat Mx1, was able to inhibit the rhabdovirus vesicular stomatitis virus (VSV) and the bunyavirus Rift Valley fever virus (RVFV) known to replicate in the cytoplasm of infected cells. Thus, cotton rats possess two Mx proteins that have selective antiviral activity that depends on their intracellular localization. We conclude that the Mx status of cotton rats differs from that of conventional inbred mouse strains, which are known to have defective Mx genes. Therefore, cotton rats are a suitable animal model to study experimental infections with FLUAV and other RNA viruses.