info@insilico.world

Development of an orthopaedic treatment models for in silico trials

To apply to this position, candidates must wait for a formal public call that will be open at the University of Bologna; meanwhile, expressions of interest and CVs may be sent to info@insilico.world

PhD position now open in the PhD Programme Health & Technology

Project title: Development of an orthopaedic treatment models for in silico trials

Project description:
The aim of the project is to develop an in silico model of a new intervention, pharmacological or surgical, to be used in in silico trials to assess the safety / efficacy of such new intervention, starting from experimental results obtained with pre-clinical animal studies.
An In Silico Trial requires a computer model of the underlying physiology, a model of the disease progression, and a model of how the intervention to be tested change such progression, and interacts with the physiological sub-system.
Models of intervention are quite easily developed from early clinical data, but in many concrete applications, it would be more useful to have a first prediction of efficacy before any human testing starts, when only results from animal experiments are available.
We plan to use a standard osteointegration rabbit model, and an ovariectomised mice osteoporosis model as sources of experimental information, from which to develop the intervention model.

Project objectives:

  1. Develop an in silico model of the animal experiment and validate it against animal experimental results.
  2. Develop the intervention model in humans, and validate it using retrospective clinical data on well-known interventions.
  3. Use results from animal models and clinical studies on previous interventions to develop and validate a transfer function that can translate the bone biology response to the intervention seen in the animal model into the human

Applicants must have:
– MSc degree (or equivalent 5-years degree) in biomedical engineering or mechanical engineering or in one the the following: engineering, physics, mathematics, computer science, chemistry, materials science or related disciplines
– Previous experience with finite element analysis; previous work on bone biomechanics
– Good written and spoken English

Tutors:
Prof. Marco Viceconti (first supervisor), Department of Industrial Engineering
Dott.ssa Milena Fini, Director of the Surgical Sciences and Technologies Lab, Rizzoli Orthopaedic Institute

Rationale and scientific background:

Every time a new intervention is developed, its safety and efficacy are first tested using the in vitro and in vivo animal models, and then in human clinical trials. Unfortunately, the passage from animal model to a human population is often not smooth, sometimes even resulting in a phase III clinical trial failure (e.g., Novartis’ SCM021 drug), with consequent time and money losses. Nonetheless, animal testing for osteoporosis drugs and prosthesis material conducted on small animals (mice and rabbits) is indeed an important source of information about physiological system response to the treatment; what is lacking is a reliable “scaling function” to transfer such information from animal to human physiological models.
Prof Viceconti’s group developed some of the first computer models to predict the risk of aseptic loosening in orthopaedic implants (Viceconti, 2004), and more recently computer models to predict the risk of femoral fracture in osteoporosis patients (Viceconti, 2019). In collaboration with the group of Prof Dall’ara (U. Sheffield, UK) we developed a model of osteoporosis treatment effect on bone strength in murine models (Lu, 2017). Recently it was shown the good predictive accuracy of these models (Oliviero, 2021). Similarly, an on-going collaboration with Dr Fini (Rizzoli Institute) the group is developing a computer model of the bone-implant osteointegration tests in rabbits.
This extensive research background provides the necessary support for such an ambitious project.
 
Viceconti, 2004. https://doi.org/10.1007/bf02345207
Viceconti, 2019. https://doi.org/10.1007/s11914-018-0438-8
Lu, 2017. https://doi.org/10.1016/j.jmbbm.2017.07.034
Oliviero, 2021. https://doi.org/10.1016/j.jmbbm.2020.104190

Preliminary results:

Prof Viceconti’s team has developed over the years various computational models to simulate bone biomechanics, from total hip replacement prosthesis osseointegration to patient-specific femur neck fracture risk due to low-energy side-fall.
The work done with the Sheffield partners (Lu, 2017) provide us a starting point for the animal-human translation function for parathyroid hormone treatments, for which extensive clinical studies are also available (e.g. for Eli Lily Forseo, Teriparatide).
The access to the regional RIPO outcome registry (Registro dell’implantologia Protesica Ortopedica) can provide extensive retrospective data on joint prostheses that failed for aseptic loosening; cross-referencing this database with the HipOp CT collection we can identify cases for which a pre-operative CT scan and a surgical planning are available, and that later failed for aseptic loosening.  We will be able to use these data to generate patient-specific models and use the rabbit experiment data to calibrate the osteointegration potential for the specific implant coating used in that device, again providing an experimental setup to validate animal human translation fuctions.

Research project including methodology

1. Perform a retrospective literature research on preclinical and clinical trials of bone-targeting pharmacological and/or prosthetic treatments and select some of them to track down their development paths.
2. Cross-reference the Sheffield data on murine response to PTH treatment with efficacy results from clinical trials of teriparatide, to develop a first validation set for our animal-human translation function for bone drugs.
3. Cross-reference the RIPO registry with the HipOp collection to find suitable cases to form a validation set for our animal-human translation function for osteointegration.
4. Use the virtual cohorts to simulate the preclinical and clinical trials.
5. Develop algorithms to predict clinical trial results starting from preclinical trial data.
6. Validate such algorithms against data from the literature.

Innovation potential

If successful, this project will result in a stronger informative power and a better interpretation of the results of animal tests aimed at human bone-related pharmaceutical and/or surgical interventions. This advancement will result in better designed preclinical and clinical trials, ultimately leading to shorter times and reduced costs for the development of medical treatments.

Research environment

The project will be conducted at the Medical Technology Laboratory, in Rizzoli Orthopaedic Institute.
The In Silico Medicine group has an active collaboration with the Surgical Sciences and Techniques group in Rizzoli’s institute about an animal experimentation reduction regional project.

Main equipment

Computational infrastructure of the In Silico Medicine team lead by Prof Viceconti. Candidate will also have access to the Marconi HPC system of Cineca, through an ISCRA grant.

Additional fundings

The entire scholarship will be funded from Prof Viceconti budget in the In Silico World project.

International collaborations for the project

– Validation of PTH treatment prediction in murine animal models – Insigneo Institute, University of Sheffield (UK) – Dr Enrico Dall’Ara

Expected results and applications to human pathology and therapy

If validated, these animal-to-human predictive models can be leveraged to provide evidence to regulatory agencies and to develop treatments that reach higher safety and effectiveness.