Clinical translation of a mesenchymal stromal cell-based therapy developed in a large animal model and two case studies of the treatment of atrophic pseudoarthrosis

Abstract

Pseudoarthrosis is a relatively frequent complication of fractures, in which the lack of mechanical stability and biological stimuli results in the failure of bone union, most frequently in humerus and tibia. Treatment of recalcitrant pseudoarthrosis relies on the achievement of satisfactory mechanical stability combined with adequate local biology. Herein we present two cases of atrophic pseudoarthrosis that received a tissue-engineering product (TEP) composed of autologous bone marrow-derived mesenchymal stromal cells (BM-MSC) combined with deantigenized trabecular bone particles from a tissue bank. The feasibility of the treatment and osteogenic potential of the cell-based medicine was first demonstrated in an ovine model of critical size segmental tibial defect. Clinical-grade autologous BM-MSC were produced following a good manufacturing practice-compliant bioprocess. Results were successful in one case, with pseudoarthrosis resolution, and inconclusive in the other one. The first patient presented atrophic pseudoarthrosis of the humeral diaphysis and was treated with osteosynthesis and TEP resulting in satisfactory consolidation at month 6. The second case presented a recalcitrant pseudoarthrosis of the proximal tibia and the Masquelet technique was followed before filling the defect with the TEP. This patient presented a neuropathic pain syndrome unrelated to the treatment that forced the amputation of the extremity 3 months later. In this case, the histological analysis of the tissue formed at the defect site provided evidence of neovascularization but no overt bone remodelling activity. It is concluded that the use of expanded autologous BM-MSC to treat pseudoarthrosis was demonstrated to be feasible and safe, provided that no clinical complications were reported, and early signs of effectiveness were observed.

Evaluation of a cell-based osteogenic formulation compliant with good manufacturing practice for use in tissue engineering

“…On the other hand, the surgical collection of autologous bone is highly associated with morbidity (4), which in some cases can be overcome by using allogeneic, decellularized human bone from tissue banks. However, such strategy lacks the benefits associated to the regenerating activity displayed by osteogenic cells, which have been demonstrated to be a key factor in our hands, after its successful use in animal models and clinical cases (5,6), in accordance with the "diamond concept" (1). In fact, autografts are preferred for treating large bony defects even when bony tissue from tissue bank is available.…”

Osteogenic commitment of Wharton’s jelly mesenchymal stromal cells: mechanisms and implications for bioprocess development and clinical application

“…The development of new treatments for bone-related diseases resulting from trauma or pathophysiological age-, sex-or infection-associated bone resorption has become a priority in the field of regenerative medicine [1][2][3][4]. In this context, autologous cell-based therapy has been presented as a promising approach to promote bone regeneration in both pre-clinical and clinical settings [5][6][7][8]. However, their clinical translation needs the delivery of safe and efficacious products, which can be largely hampered by age and comorbidities of the cell donor [9][10][11][12][13].…”

Evaluation of a cell-based osteogenic formulation compliant with good manufacturing practice for use in tissue engineering

“…On the other hand, the surgical collection of autologous bone is highly associated with morbidity (4), which in some cases can be overcome by using allogeneic, decellularized human bone from tissue banks. However, such strategy lacks the benefits associated to the regenerating activity displayed by osteogenic cells, which have been demonstrated to be a key factor in our hands, after its successful use in animal models and clinical cases (5,6), in accordance with the "diamond concept" referring to the need of osteoinductive mediators, osteogenic cells, an osteoconductive scaffold and mechanical stability (1).…”

“…Therefore, when this approach is not feasible (i.e. re-interventions, donor site morbidity, infections), the use of osteogenic cells isolated from bone marrow (BM), either as bulk concentrates or enriched in multipotent mesenchymal stromal cells by ex vivo expansion, is an alternative that has already been explored in large animal models, and also in early Phase I/II clinical trials with encouraging results (5)(6)(7)(8). It is particularly interesting the development of products that combine culture-expanded multipotent Mesenchymal Stromal Cells (MSC) and scaffolds, namely "Tissue Engineering Products" (TEP), resulting in a new medicinal entity with osteogenic potential that is specifically regulated as advanced therapy and needs to comply with pharmaceutical regulations (9).…”

“…Particulated decellularized/deantigenized bone matrix from human cadaveric donors can be found commercially on different size formats and are commonly used in the clinics for bone mass augmentation. Small particles, like we employed in the present study, make possible to increase the surface area so, their natural osteoinductive and osteoconductive properties are available to cells embedded in fibrin hydrogels(5). The non-cellular components of the TEPs have the capacity to generate a biological environment that ensures the supply of nutrients to the cells and facilitates their regenerative function.…”