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MesopOrous matrices for localiZed pH-triggered releAse of theRapeuTic ions and drugs

Periodic Reporting for period 3 - MOZART (MesopOrous matrices for localiZed pH-triggered releAse of theRapeuTic ions and drugs)

Reporting period: 2018-11-01 to 2019-10-31

In pathological situations, where bacterial infection is a common, often highly serious complication (e.g. osteomyelitis following bone reconstructive surgery and infected chronic wounds), conventional treatments include systemic antibiotic administration, surgical debridement, wound drainage and implant removal (if present). The over-use of antibiotics (with the development of antibiotic resistance) is a world-wide problem hence the drive for alternative antimicrobials is a must.
5-10% of the overall fractures result in a delayed bone healing or in a non –union fracture. The current clinical approach is not always successful and patients may suffer from extra surgeries and may experience disability and pain.
The strategy proposed in MOZART to solve these problems is the introduction of a local, dual ion/drug release smart system into the injured site to improve the therapy. Hence, the objective of the MOZART project is to develop a library of innovative nanomatrices (NMs) to be used as a smart platform technology for effective, highly targeted therapies in the biomedical field. The developed NMs are characterized by innovative compositions containing several therapeutic ions able to elicit a specific biological response and also by the presence of a high volume of nanopores that can be exploited to upload a specific payload.
The advantages of such a treatment include a synergistic effect between ions and biomolecules released from the biomaterial, high delivery efficiency, continuous action in situ, fine control of the amount of therapeutic agents incorporated (and released), reduced toxicity and overall convenience to the patients. In order to vehicle the NMs in the surgical site avoiding their dispersion, a thermosensitive, resorbable and injectable gel has been developed. As proof of concept, the MOZART project had addressed two well-defined and global clinical challenges, i.e. non-healing bone and chronic non-healing skin wounds, developing two different medical devices.
In such pathological states, with particular reference to wound infection, an endogenous pH value change due to inflammatory or hypoxic conditions was found to be present, with niche of both acidic and basic pHs and has been used to trigger the drug release. In MOZART the synergistic release of ions and drugs has been exploited to demonstrate the potential for a radical improvement in therapy for those patients with chronic skin wounds that fail to heal and bone healing defects that resist conventional therapy. Both these fields involve a very large patient numbers which are increasing with an ageing population.
The consortium worked on the development of mesoporous glasses doped with several therapeutic ions such as silver, cerium, copper and strontium and on various ordered mesoporous carbons containing silver. Overall 42 different NMs has been developed and fully characterized offering a library of solutions potentially exploitable also for application different than the two addressed in the MOZART project. Different method for payload incorporation has been tested at both research and industrial partner facilities and the one leading to the highest loading yield as well as the highest reproducibility has been selected to proceed with the project activities. In vitro test results showed very promising results for some of the developed NMs and the most interesting ones have been transferred to TRL5 production and has been selected to be tested in an in vivo setting for the bone healing device and the wound healing device. Self- immolative coating has been developed in order to allow the payload release only upon a pH variation. Different thermosensitive gels able to incorporate the NMs and to vehicle them to the clinical site have been fully developed: they can be easily injected, they gelify at human body temperature and they are resorbable. Two medical devices have been designed and prototypes has been obtained at TRL5, sterilised, packaged and tested in the two chosen clinical settings (delayed bone healing and chronic wound), obtaining a very positive outcome. A board of clinicians has been involved in order to evaluate the two developed devices and based on their feedbacks, adjustments of the device packaging and mixing procedure have been implemented.
Detailed cost estimations have been made for each material and include the costs of chemicals employed in the synthesis (precursors, templating agent, solvent etc), energy consumption during each process, waste management (disposal of solvents or solid garbage etc.), sterilisation and packaging of the MOZART devices. Product scalability is not the only factor in industrial applications, it is also important to maintain efficiency in cost and resource usage. Safety consideration have been constantly considered as well as standards and regulatory matters.
15 papers have been published in international Journals with high impact factors and other two have been submitted before the end of the project. Two workshops have been organised, one for a more scientific audience and the second one for the industrial community.
From an overall market analysis, a plethora of commercial products related to chronic wound treatment as well as bone fracture treatment have been identified and put into categories, forming a best-in-class benchmark list that have been used by the consortium as reference to develop the MOZART solutions and as control to assess the potential of the developed solutions. For the bone healing application, at present, when a delay in bone healing occurs, this leads to a long and difficult treatment which causes pain and considerable cost burden to the health system care. MOZART aims to alleviate all these highly undesirable effects by preventing the occurrence of the cause of the delay, leading to a radical improvement in therapy. MOZART has the ambition to develop medical devices based on a novel NMs concept that will allow a timely and highly effective anti-inflammation treatment when properly coupled with an early recognition of impaired bone healing. For the wound healing application, all products currently on the market work on a single-modality effect (i.e. target an anti-inflammatory effect or anti-bacterial activity or a pro-angiogenic effect). In MOZART, the combination of drug and therapeutic ions will synergistically work together to obtain a multi-modality device. Due to the chronic nature of non-healing wounds, development of antibiotic-resistant bacterial strains is often found in these patients. Exploitation of therapeutic inorganic ions as antimicrobial agents released from MOZART NMs will allow the shortcomings of antibiotics to be successfully overcome.
MOZART NMs have been translated to TRL5 using a robotic cell developed able to produce 500g/day (TRL5) compared to 1g/day (TRL3). In such a way, a safe and resource efficient manufacturing process has been developed, filling the gap between academic and industrial settings concerning the production of these nanomaterials, in terms of industrial and regulatory standards.
Validation of the bone healing device - MOZART project
Project logo
The MOZART platform of nanomatrices
Outreach activities - MOZART project
Dissemination activities - MOZART project
Bone healing device - MOZART project