Type I collagen is used widely as a biomaterial. The structure of collagenous biomaterials, including pore sizes and general architecture, can be varied by a number of techniques. In this study, we developed a method to construct flat fibrillar type I collagen scaffolds, 6 cm in diameter and with a radially orientated pore structure, by the use of directional freezing. Different methodologies were tested, the optimal one being freezing of a collagen suspension inside-out, using a centrally positioned liquid nitrogen-cooled tube. Pore sizes could be varied by the use of different tube materials. Use of aluminium tubes resulted in radial scaffolds with a pore size of 20-30 µm, whereas use of stainless steel produced radial scaffolds with 70-100 µm pore sizes. Brass- and copper-based tubes produced scaffolds with less homogeneous radial pores, pore sizes being 90-100 and 50-80 µm, respectively. Fibreglass tubes gave even less uniformity (pore size 100-150 µm). Scaffolds were free of cracks, except in case of aluminium. Scaffolds with a radial inner structure may be especially suitable for tissue engineering of organs with a radial scaffold structure, such as the diaphragm.

Introduction Patients with congenital vascular malformations often suffer from an impaired quality of life (QoL) because of pain and functional disabilities. Previous studies have shown that the mTOR inhibitor sirolimus can reduce complaints and improve QoL in some patients. High target levels of sirolimus of 10–15 ng/ml were well tolerated; however, in a relative high percentage of patients sirolimus caused serious adverse events (AEs). Methods A case series of 12 patients with therapy-resistant low-flow vascular malformations was treated with sirolimus, using low target levels of 4–10 ng/ml. Efficacy of sirolimus was evaluated in regard to pain symptoms using the visual analogue scale/numeric rating scale and patients reported QoL. To rule out a placebo effect of sirolimus, sirolimus was stopped after a certain time point and reintroduced as soon as complaints returned. Adverse events were closely monitored and graded using the Common Terminology Criteria for Adverse Events (CTCAE) grading. Results An improvement in symptoms was seen in 92% ( n = 11/12) of patients. In nine patients pain complaints returned. Seven out of nine of them (78%) again experienced a reduction of symptoms after restarting sirolimus treatment. Despite low target levels, these response rates are comparable to those found in the literature using higher target levels of sirolimus. However, significantly less serious AEs were observed with low dose sirolimus, suggesting low dose sirolimus might be safer. Unfortunately, young adolescent female patients developed serious menstrual disturbances during treatment with low dose sirolimus. We describe this adverse event for the first time in patients with congenital vascular malformations and this might be specifically related to low dose sirolimus. Conclusions Low dose sirolimus showed a high efficacy in patients with therapy-resistant and low-flow malformation, with a lower incidence of serious adverse events. At the same time a new adverse event, namely menstrual cycle disturbance, was observed in young adolescents, indicating the need for caution when sirolimus is given. This is extremely relevant to patients with low-flow vascular malformation, who are likely to require lifelong treatment for their condition. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01758-y.

Bioequivalence could not be demonstrated for a crushed and suspended tablet or a crushed and suspended tablet with oral intake of enteral nutrition compared with whole-tablet TRI with fasting. Both scenarios led to higher dolutegravir exposure, but this did not exceed exposure after intake with food or in twice-daily dosing. In our opinion, TRI can be crushed for patients with swallowing difficulties and can be simultaneously administered with enteral nutrition.

Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects.Methods: A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m 2 every 24 or 48 hours according to their age. Prednisone was added to the therapy for additional effect in 4 patients.Results: In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen. Conclusion:Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments.

The clinical presentation of patients with slow-flow vascular malformations is very heterogeneous. High clinical burden and subsequent reduced health-related quality of life is something they have in common. There is an unmet medical need for these patients for whom regular treatments like surgery and embolization are either insufficient or technically impossible. Sirolimus has been reported to be effective and overall well-tolerated in most patients. However, the main limitation of sirolimus is the reported high toxicity, especially when target levels of 10-15 ng/mL are being used. We report the results of a phase IIB single-arm open-label clinical trial consisting of 68 (67 in the challenge phase and 68 in the rechallenge phase) evaluable patients (children n = 33 and adults n = 35) demonstrating that treatment with low sirolimus target levels (4-10 ng/mL) is effective