Sustained-release implants for intraperitoneal cisplatin delivery

Thesis: Ph. D. in Medical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2018.Cataloged from PDF version of thesis.Includes bibliographical references (pages 217-226).The objective of this work was to develop materials for continuous low-dose delivery of cisplatin directly into the abdomen, also known as intraperitoneal (IP) chemotherapy. IP chemotherapy can help treat peritoneal metastasis in many advanced gynecologic and gastrointestinal cancers and has shown particular promise in treating advanced ovarian cancer. It is however tremendously underutilized because it requires a lot of resources and the current technology and maximum tolerated dose regimen cause complications and severe toxicity to patients. We previously showed that continuous low-dose IP cisplatin delivery via an implanted diffusion-based reservoir device can be as effective as and less toxic than intermittent maximum tolerated dose IP injections. To translate this work to a clinically relevant implantable system, we developed composite materials that can deliver cisplatin at a continuous low dose that is tunable. The materials were mechanically well suited for placement in the abdomen and were evaluated for in vitro bioactivity, in vivo tolerability and in vivo ability to deliver platinum to key abdominal organs with promising results. Dosing studies with different material dimensions helped identify a dose to pilot treatment of ovarian cancer in human xenograft-bearing mice. The implications of more accessible and affordable IP chemotherapy are especially important in countries with limited resources. Design reviews and a clinician survey in India reveal eagerness for early adoption of new technologies and dosing regimens to treat peritoneal metastasis and show promise for utilization of our implant in the developing world. The work described in this thesis carries implications for the treatment of advanced ovarian cancer and peritoneal metastasis of other tumors affecting millions of patients worldwide and may help with the management of nonmalignant conditions with abdominal involvement.by Aikaterini Mantzavinou.Ph. D. in Medical Engineerin

Investigation of alternative management scenarios of domestgic water

333 σ.Εθνικό Μετσόβιο Πολυτεχνείο--Μεταπτυχιακή Εργασία. Διεπιστημονικό-Διατμηματικό Πρόγραμμα Μεταπτυχιακών Σπουδών (Δ.Π.Μ.Σ.) "Επιστήμη και Τεχνολογία Υδατικών Πόρων"Η παρούσα μεταπτυχιακή διπλωματική εργασία έχει ως στόχο τη διερεύνηση εναλλακτικών σεναρίων διαχείρισης των υδάτινων ροών που παράγονται σε επίπεδο κατοικίας. Ειδικότερα, εξετάζονται 5 διαφορετικοί τύποι ιδεατών, μη - υφιστάμενων κατοικιών, εκ των οποίων : α) μονοκατοικία με κήπο και σύνδεση σε δίκτυο αποχέτευσης, β) μονοκατοικία με κήπο - χωρίς σύνδεση σε δίκτυο αποχέτευσης, γ) μονοκατοικία χωρίς κήπο, με σύνδεση σε δίκτυο αποχέτευσης, δ) πολυκατοικία με κήπο και σύνδεση σε δίκτυο αποχέτευσης και ε) πολυκατοικία με κήπο - χωρίς σύνδεση σε δίκτυο αποχέτευσης. Τη βάση για το σχεδιασμό των διαχειριστικών σεναρίων αποτελεί η αρχή της μείωσης της υδατικής κατανάλωσης και κατά δεύτερον η κατά το δυνατόν επαναχρησιμοποίηση ορισμένων οικιακών υδάτινων ροών και συγκεκριμένα του βρόχινου νερού, γκρίζου νερού και μικτών υγρών οικιακών αποβλήτων. Τα διαχειριστικά σενάρια παρουσιάζονται αναλυτικά με ταυτόχρονη περιγραφή του εξοπλισμού που απαιτείται για την υλοποίησή τους, για τον οποίον παρατίθενται στοιχεία κόστους, που προέκυψαν έπειτα από έρευνα αγοράς. Κάθε μια από τις 5 ομάδες διαχειριστικών σεναρίων (που προκύπτουν για τους 5 προαναφερθέντες τύπους μη - υφιστάμενων κατοικιών) αξιολογείται με βάση α) τις ποσότητες των παραγόμενων οικιακών υδάτινων ροών που συνεπάγεται η εφαρμογή τους και β) οικονομικά κριτήρια, τα οποία αναφέρονται στο συνολικό κόστος των σεναρίων (κόστος κτήσης, εγκατάστασης, λειτουργίας, συντήρησης και ύδρευσης – αποχέτευσης) 1)με βάση την ισχύουσα κατάσταση αλλά και 2) θεωρώντας το ενδεχόμενο αύξησης της αξίας του νερού όπως επίσης και 3) το ενδεχόμενο χορήγησης κρατικής επιδότησης. Η αξιολόγηση των ομάδων διαχειριστικών σεναρίων αποσκοπεί στην ανάδειξη της βέλτιστης λύσης σε κάθε περίπτωση. Η συνολική θεώρηση των αποτελεσμάτων της αξιολόγησης όλων των ομάδων διαχειριστικών σεναρίων έδειξε σε πρώτη βάση ότι τα σενάρια που προτείνουν την εξοικονόμηση νερού στις οικιακές συσκευές αποτελούν την πιο φθηνή λύση με ένα μέσο προς χαμηλό ποσοστό εξοικονόμησης πόσιμου νερού και μια μέση φόρτιση του δικτύου αποχέτευσης σε σχέση με τα υπόλοιπα σενάρια. Ωστόσο, εκτός από τα σενάρια εξοικονόμησης, αναδείχθηκαν και κάποια άλλα, διαφορετικά για κάθε περίπτωση κατοικίας. Ειδικότερα, αναφορικά με την κατοικία με κήπο και σύνδεση σε δίκτυο αποχέτευσης, ένα σενάριο που συνδυάζει εξοικονόμηση νερού και χρημάτων, είναι εκείνο που προτείνει αξιοποίηση γκρίζου νερού για άρδευση και εξοικονόμηση νερού στις οικιακές συσκευές. Το συγκεκριμένο σενάριο γίνεται πιο οικονομικό από την οικονομική λύση σε περίπτωση αύξησης της τιμής του νερού κατά 5% ή χορήγησης κρατικής επιδότησης 300 €. Η εφαρμογή οποιουδήποτε άλλου σεναρίου – και κυρίως των σεναρίων με υψηλά ποσοστά εξοικονόμησης πόσιμου νερού και φόρτισης του δικτύου αποχέτευσης (σενάρια που προτείνουν την αξιοποίηση βρόχινου και γκρίζου νερού) - είναι εφικτή υπό το ενδεχόμενο μιας υψηλής αύξησης της αξίας του νερού (> 80%) ή μιας υψηλής επιδότησης (> 7,000 €). Επιπλέον, από το σύνολο των σεναρίων που αναφέρονται σε μια μονοκατοικία με κήπο - χωρίς σύνδεση σε δίκτυο αποχέτευσης, αναδείχτηκε το σενάριο που προτείνει εξοικονόμηση νερού στις συσκευές και σύστημα επεξεργασίας των οικιακών λυμάτων, ενώ το σενάριο που προτείνει εξοικονόμηση νερού (οικιακές συσκευές) και επαναχρησιμοποίηση του γκρίζου νερού για άρδευση, επιτυγχάνει χαμηλότερη υδατική κατανάλωση και μπορεί να υλοποιηθεί με μια ενδεχόμενη αύξηση της τιμής του νερού κατά 20% ή με επιχορήγηση 800 € για κάθε νοικοκυριό. Στην περίπτωση της μονοκατοικίας χωρίς κήπο αλλά με σύνδεση σε δίκτυο αποχέτευσης, τα μόνα οικονομικά προσιτά για το νοικοκυριό σενάρια είναι εκείνα που προτείνουν την εξοικονόμηση νερού στις οικιακές συσκευές. Πιθανή αύξηση της τιμής του νερού ή το ύψος της κρατικής επιδότησης που θα καταστήσουν υλοποιήσιμο κάποιο σενάριο που προτείνει την αξιοποίηση κάποιας υδάτινης οικιακής ροής και που επιτυγχάνει μεγαλύτερη εξοικονόμηση πόσιμου νερού, ξεπερνά κατά πολύ το 150% και τα 10,000 € αντίστοιχα. Στην περίπτωση του διαμερίσματος σε πολυκατοικία με κήπο και σύνδεση σε δίκτυο αποχέτευσης, όλα τα προτεινόμενα σενάρια συνεπάγονται αύξηση των δαπανών του νοικοκυριού του διαμερίσματος με το πιο προσιτό να είναι το σενάριο που προτείνει εξοικονόμηση νερού στις οικιακές συσκευές. Μια λύση που μπορεί να γίνει επιλέξιμη με τη χορήγηση μιας λογικής κρατικής επιδότησης είναι το σενάριο που προτείνει την αξιοποίηση του βρόχινου νερού της πολυκατοικίας για άρδευση του κήπου (9,000 € / πολυκατοικία). Τέλος, για το νοικοκυριό που διαβιεί σε διαμέρισμα πολυκατοικίας με κήπο - χωρίς σύνδεση σε δίκτυο, καταλήγουμε στο συμπέρασμα ότι όλα τα σενάρια πέραν του σεναρίου εξοικονόμησης νερού στις οικιακές συσκευές, επιφέρουν αύξηση των δαπανών του νοικοκυριού. Επίσης, η επιλογή του συγκεκριμένου σεναρίου θεωρείται καλή καθώς εξοικονομεί ταυτόχρονα μια μέση ποσότητα νερού. Αντίθετα, για την υλοποίηση των σεναρίων (εκτός από το σενάριο εξοικονόμησης) που επιτυγχάνουν μεγαλύτερη εξοικονόμηση πόσιμου νερού, η χορήγηση επιδοτήσεων ανά πολυκατοικία ξεπερνά τις 20,000 €, ενώ μια αύξηση της τιμής του νερού που θα τα καθιστούσε οικονομικά ενδιαφέροντα υπερβαίνει κατά πολύ πάνω το 150%.The present M. Sc thesis aims to investigate some alternative management scenarios of the aquatic flows produced in a typical residence. More specifically, 5 groups of ideal dwellings are examined : a) a detached residence with garden and a connection to the sewerage (11 scenarios), b) a detached residence with garden – without a connection to the sewerage (8 scenarios), c) a detached residence without garden – occupying a connection to the sewerage (5 scenarios), d) a flat in a block of flats with garden and a connection to the sewerage (4 scenarios) and e) a flat in a block of flats with garden – without a connection to the sewerage (5 scenarios). The basis on which the design of the water management scenarios was conducted, was, first of all, the reduction of water consumption and secondly, the reuse and recycling of some domestic aquatic flows. Especially, referring to the reuse, the aquatic flows examined were the rainwater, the greywater and the mixed wastewater of a typical residence. The water management scenarios are presented in detail, including a complete description of the prerequisite technology followed by data regarding its cost, extracted after extensive market research. Each one of the 5 groups of water management scenarios is evaluated on the basis of a) the quantities of the domestic aquatic flows, produced after the scenario implementation and b) economic criteria regarding the total cost of the scenario performance (acquisition cost, functional and maintenance cost, cost of water supply and sewerage). These economic criteria are analysed regarding i) the present situation (current prices), ii) the possibility of an increase in the water price (0% -150%) and iii) the possibility of granting a state subsidy to each detached residence of block of flats. Generally, the evaluation of all water management scenarios targets towards the revelation of the optimal solution for each type of dwelling. The overall consideration of the investigation procedure of the alternative water management scenarios leads to the conclusion that the most profitable and preferable scenarios are those that suggest the implementation of water efficient devices in the residence. Moreover, these scenarios lead to medium to low water conservation and to medium loading of the sewerage system. However, apart from these scenarios, the investigation showed some other – different for each type of dwelling - that could be interesting and smart choices for the household. Especially, referring to a detached residence with garden and a connection to the sewerage, a good choice that saves money and water, is the scenario that suggests water efficient devices and the reuse of greywater for garden watering. This particular scenario is more inexpensive than the zero scenario in case of a 5% increase in the water price or a 300 € state subsidy. The implementation of any other scenario in this type of dwelling - and especially scenarios achieving high percentages of water conservation and low loading of the sewerage system – are viable only in case of very high increase of the water price (> 80%) or generous state subsidies (> 7,000 €). In addition, regarding the group of scenarios for a detached dwelling with garden – without a connection to the sewerage system, it is concluded that the best scenario in this case is the one that proposes water efficient devices in combination with the treatment of mixed wastewater. However, the scenario that suggests the implementation of water efficient devices and the reuse of greywater for garden watering achieves lower water consumption and can be implemented regarding a potential and realistic 20% increase in the water price as well as a 800 € state subsidy for each household. In the case of a detached dwelling without garden – with a connection to the sewerage, the only economically interesting scenarios are those which suggest the use of water efficient devices. A potential increase in the water price or the amount of the state subsidy that would induce householders to implement some other water management scenarios of this group, far exceeds 150% and 10,000 € / household respectively. Furthermore, in the case of a block of flats with garden and a connection to the sewerage system, all the suggested water management scenarios tend to increase the annual household (“aquatic”) expenses compared to the ones of the zero scenario. The most interesting scenario is the one that suggests the use of water efficient devices. Another scenario that could be selected if there was granted a 9,000 € state subsidy per block, is the one that proposes the use of rainwater for garden watering. Finally, as far as it regards a block of flats with garden – without a connection to the sewerage system, all the suggested scenarios are more expensive than the zero one, except from the one that suggests the use of water efficient devices. The selection of this particular scenario is considered as good because its performance leads to a considerable – compared to the other scenarios of the group - decrease in domestic water consumption. The implementation of any other scenario of this group demands a state subsidy of more than 20,000 € per block or an increase in the water price that far exceeds 150%.Παναγιώτα Γ. Μαντζαβίνο

Design thinking in development engineering education: A case study on creating prosthetic and assistive technologies for the developing world

A human-centered design thinking approach has been applied to a course at the MIT D-Lab on creating low-cost prosthetic and assistive devices for the developing world. Teams of students with diverse backgrounds are paired with international stakeholders and industry partners to tackle real-world prosthetic technology needs, learn the design process through interactive lectures and workshops in the classroom, and are given the opportunity to conduct testing of the prototypes generated during the semester at field sites around the globe. The revamped course offers a fully immersive design experience that extends beyond the classroom and the semester by stimulating further research, inspiring and motivating student professional development, raising additional grant money and generating peer-reviewed publications and intellectual property. A multifaceted and nontraditional engagement with industry partners, as developed in our course, provides a novel and promising model for development engineering courses to afford unique opportunities to their students. As a result of our new course initiatives mean student enrollment has tripled and total project continuation beyond the end of the class has exceeded 60%. In this paper, we outline our framework for incorporating human-centered design thinking into development engineering education, provide outcomes, and present case studies of select projects that have successfully emerged from our course. Our novel pedagogical approaches and collaborative efforts showcase a promising way to engage students in impact-focused project-based learning with long-term benefits for their projects as well as their career development opportunities. Keywords: Design thinking, Engineering education, International development, Project-based learnin

Global surgery hackathons: A case study from Pakistan

Background: Hackathons aim to solve problems in a selected field by bringing together people from multiple domains and combining their expertise. Global surgery is an emerging field with a huge burden of disease and massive implications for bettering health care. In this study, we describe the first Global Surgery Hackathon held in Pakistan and analyze the impacts of the hack and post-hack incubation. Methods: This research study used data collected from a Hackathon held at the Aga Khan University (AKU) in Karachi, Pakistan, and progress from the post-hack incubation teams. Data were collected from applications, from sign-in attendance, via evaluation forms, and milestone tracking of the incubation teams. A list of factors such as sectors addressed by winning projects and grants received was made. Results: The evaluations provided by the participants were positive, with mean scores of 4.00 (SD = .78) out of 5 on a Likert scale. Pitches made (n = 69, 68%) by the 109 participants were sorted into 5 categories: workplace, access, quality, safety, and design. Fifteen teams were formed, out of which 5 were accepted for incubation. All teams had a minimum viable product at the one-year mark. Conclusion: Hackathons are a reliable way to come up with effective solutions for targeted problems in various areas of health care and using the methodology of a Hackathon, a pool of low-cost, innovative solutions can be generated. These solutions can definitely impact health outcomes, especially for the field of global surgery. Further statistics should be collected to affirm the incubated solutions’ impact

Sustained, low-dose intraperitoneal cisplatin improves treatment outcome in ovarian cancer mouse models

Intraperitoneal (IP) chemotherapy for ovarian cancer treatment prolongs overall survival by 16 months compared to intravenous chemotherapy but is not widely practiced due to catheter-related complications and complexity of administration. An implantable, nonresorbable IP microdevice was used to release chemotherapeutic agent at a constant rate of approximately 1.3 μg/h in vitro and 1.0 μg/h in vivo. Studies conducted in two orthotopic murine models bearing human xenografts (SKOV3 and UCI101) demonstrate that continuous dosing reduces tumor burden to the same extent as weekly IP bolus drug injections. Treatment-induced toxicity was quantified via body weight loss and complete blood count. The microdevice resulted in significantly less toxicity than IP bolus injections, despite administration of higher cumulative doses (total area under the concentration-time curve of 3049 ng day/mL with the microdevice vs. 2118 ng-day/mL with IP bolus injections). This preclinical study supports the concept that reduced toxicity with similar efficacy outcomes can be achieved by continuous dosing in ovarian cancer patients currently treated with IP therapy

Single compartment drug delivery

Drug design is built on the concept that key molecular targets of disease are isolated in the diseased tissue. Systemic drug administration would be sufficient for targeting in such a case. It is, however, common for enzymes or receptors that are integral to disease to be structurally similar or identical to those that play important biological roles in normal tissues of the body. Additionally, systemic administration may not lead to local drug concentrations high enough to yield disease modification because of rapid systemic metabolism or lack of sufficient partitioning into the diseased tissue compartment. This review focuses on drug delivery methods that physically target drugs to individual compartments of the body. Compartments such as the bladder, peritoneum, brain, eye and skin are often sites of disease and can sometimes be viewed as “privileged,” since they intrinsically hinder partitioning of systemically administered agents. These compartments have become the focus of a wide array of procedures and devices for direct administration of drugs. We discuss the rationale behind single compartment drug delivery for each of these compartments, and give an overview of examples at different development stages, from the lab bench to phase III clinical trials to clinical practice. We approach single compartment drug delivery from both a translational and a technological perspective.National Institutes of Health (U.S.) (Grant R37EB000244)National Institutes of Health (U.S.) (Grant K99EB016690)National Institutes of Health (U.S.) (Grant R01EB016101)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Grant W911NF-13-D-0001)Singapore. Agency for Science, Technology and ResearchNational Science Foundation (U.S.). Graduate Research FellowshipDavid H. Koch Institute for Integrative Cancer Research at MIT (Bridge Project)David H. Koch Institute for Integrative Cancer Research at MIT (Core Grant