DDRugging glioblastoma through the development of smart biomaterials

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From inception, the proposed project has been designed specifically with reference to the EPSRC HealthcareTechnologies Theme. In line with the first 'grand challenge' aim of this theme, the project is expected to tacklea number of engineering challenges to develop a new therapy, with the potential for future clinical translation.Since brain tumours are responsible for more years of life lost than any other cancer, we believe the clinicalcontext of the studies aligns strongly with the 'strong features' of the Theme's vision to focus on the highestpriority healthcare challenges. Previously developed surgically-delivered therapies for glioblastoma - the mostcommon and aggressive brain cancer - are not routinely used in the clinic due to a number of physical limitationswhich hamper their efficacy including: rapid, potentially toxic drug release profiles; physical properties includingstiffness which are not well matched with the human brain, and; the permanent, non-degradable nature ofcompounds used. A fresh, and multidisciplinary engineering perspective is required to develop new biomaterialsthat are fully attuned to the current unmet clinical need. As such, the proposed project will deal with a number ofcritical engineering challenges to provide a novel, composite biomaterial with the potential to improve patientoutcomes. Firstly, the properties of previous PLGA/PEG pastes will need to be substantially modified to enablethe delivery of a number of targeted drug therapies, and provide a stiffness much more comparable to brain thanin previous studies. Secondly, microbeads with properties that permit the ionizing radiation triggered release ofboth targeted drugs and temozolomide will need to be developed. Although we anticipate these may be based onuse of a poly-di(carboxylatophenoxy)phosphazene (PCPP) hydrogel with a selenocystamine cross-linked matrix, anumber of alternatives will be developed to provide optimal 'on/off' drug release, whilst also considering thepotential for 'drug recharge'. Thirdly, both components of the composite biomaterial will need to be improved aspart of iterative engineering process to ensure their use in combination does not adversely impact desiredproperties and to provide an overall drug release profile and duration which far exceeds materials published todate. This represents a significant challenge, but is critical to provide the durable treatment responses thatpatients desperately require. Fourthly, the project deals with the engineering challenge of developing potentialways to replenish drug compound(s) into the smart biomaterial. This provides a fresh problem, which to resolve,we expect the student will need to take inspiration from current implantable neurosurgical devices (such as anOmmaya reservoir, or a baclofen pump) and adapt these to develop a new device that can be used in conjunctionwith the smart biomaterial developed earlier in the studies. With our support, a particularly talented student maybe able to further advance this idea - for example, by developing a bioelectronic device with sensing capabilitiesto monitor drug concentration adjacent to the surgical resection cavity and alert the user when drugreplenishment is required and/or administer this in an automated manner. Finally, the studies will incorporatedevelopment of a 3D bioink printed resection cavity model to efficacy test the biomaterials against explantedglioblastoma cells or tissue. The 'to-scale' or 'near human scale' nature of this novel model will represent animportant advance in the 3D glioblastoma models our team are currently engineering and is likely to requirenumerous innovations to maintain cell viability at this scale, including integration of a 3D printed prototypevascular/perfusing network.