Cartilage Tissue Engineering
1. Regenerative properties of human nasal chondrocytes
We dedicated more than 10 years of research to characterise and regulate the processes of de- and re-differentiation of human nasal chondrocytes (NCs) in different culture models, leading to the definition of protocols for the engineering of cartilage grafts of consistent quality. The engineered cartilage implants were first used in phase I clinical trial for the reconstruction of nasal alar lobule after skin tumor excision (ClinicalTrials.gov, number NCT01242618). The study demonstrated safety and feasibility of the procedure, along with patient satisfaction. Extensive research was then conducted to assess the possibility to use NCs for the repair of cartilage also at sites different from the face. In particular we showed that adult human Hox-negative NCs could be reprogrammed to stably express Hox genes typical of articular chondrocytes upon implantation into goat articular cartilage defects. This environmental plasticity, together with several pre-clinical findings indicated that NCs have a broad regenerative potential. Indeed, in a recent first-in-human trial (ClinicalTrials.gov, number NCT01605201) we have shown the safety, feasibility and preliminary efficacy of the use of engineered cartilage based on autologous NCs for the regeneration of post-traumatic cartilage defects.
Encouraged by the results generated from the aforementioned pre-clinical and clinical studies we have started a phase II clinical trial with the objective to test the clinical efficacy of our tissue engineered cartilage graft for the repair of knee cartilage defects (ClinicalTrials.gov, number NCT02673905).
Fulco I, et al., Engineered autologous cartilage tissue for nasal reconstruction after tumour resection: an observational first-in-human trial. Lancet, 2014. 384: 337-46. Pubmed.
Candrian C, et al., Engineered cartilage generated by nasal chondrocytes is responsive to physical forces resembling joint loading. Arthritis Rheum, 2008. 58: 197-208. Pubmed.
Pelttari K, et al., Adult human neural crest-derived cells for articular cartilage repair. Sci Transl Med, 2014. 6: 251ra119. Pubmed.
Mumme M, et al., Nasal chondrocyte-based engineered autologous cartilage tissue for repair of articular cartilage defects: an observational first-in-human trial. Lancet, 2016. 388: 1985-1994. Pubmed.
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2. Generation and validation of osteochondral model to investigate mechanisms triggering osteoarthritis.
Within the context of an ongoing Swiss National Foundation (SNF) grant, we will use a microfluidic hydrogel platform to generate physiological and pathological models of osteochondral units. The model will be first exploited to elucidate mechanisms of cartilage/bone cross talk during the triggering of osteoarthritis (OA), and subsequently to screen novel OA disease-modifying compounds. Specifically, we will investigate whether factors released by nasal chondrocytes could be potentially used as OA disease-modifying compounds. For such activities we will collaborate with Dr. Marco Rasponi at the Politecnico of Milano (Italy) and Prof. Martin Ehrbar at the University of Zürich.
- Swiss National Science Foundation (project “A 3D microfluidic osteochondral model to investigate mechanisms triggering osteoarthritis and therapeutic effects of bioactive factors produced by human nasal chondrocytes”, no 310030_175660)
3. Investigations of the biological processes responsible for the plasticity of adult human nasal chondrocytes.
We are intended to assess whether adult human nasal chondrocytes (NCs) can be used for the regeneration of other cartilage types. Towards this goal, we will perform research activities intended to establish fundamental understanding of the biological processes responsible for the plasticity of NCs. In particular we are planning to establish whether Hox-negative adult NCs and embryonic Cranial Neural Crest Cells share similar transcriptomes, epigenomes and 3D chromatin architectures and assess whether NCs can epigenetically and transcriptionally adapt to different Hox-positive mesodermal derived environments. Importantly we will investigate whether these features are shared by all nasal chondrocytes or only displayed by specific subpopulations. The definition and control of the epigenetic chromatin state of nasal chondrocytes will be helpful to assess the capacity of these cells to (re)generate different type of cartilage in the human body. For such activities we will collaborate with Prof. Filippo Rijli at the Friedrich Miescher Institute for Biomedical Institute of Basel.
4. Generation of grafts to be used for the reconstruction of long-segment tracheal defects substitute.
We will investigate the capacity of nasal chondrocytes to colonize devitalized tracheal cartilage tissues previously exposed to laser perforation. Additionally we will establish proper conditions allowing efficient epithelialization of the revitalited constructs using nasal epithelial cells (i.e., cell source that can be isolated together with nasal chondrocytes from the same biopsy). The engineered epithelial-cartilage composite tissues will be finally tested for their capacity to repair experimental tracheal cartilage defects in different animal models. For such activities we will collaborate with Prof. Dieder Lardinois, head of the Department of Thoracic Surgery at University-Hospital of Basel and Prof. Heinz Redl at the Ludwig Bolzmann Institute of Vienna.