Regeneration of hyaline cartilage promoted by xenogeneic mesenchymal stromal cells embedded within elastin-like recombinamer-based bioactive hydrogels

Abstract

Over the last decades, novel therapeutic tools for osteochondral regeneration have arisen from the combination of mesenchymal stromal cells (MSCs) and highly specialized smart biomaterials, such as hydrogel-forming elastin-like recombinamers (ELRs), which could serve as cell-carriers. Herein, we evaluate the delivery of xenogeneic human MSCs (hMSCs) within an injectable ELR-based hydrogel carrier for osteochondral regeneration in rabbits. First, a critical-size osteochondral defect was created in the femora of the animals and subsequently filled with the ELR-based hydrogel alone or with embedded hMSCs. Regeneration outcomes were evaluated after three months by gross assessment, magnetic resonance imaging and computed tomography, showing complete filling of the defect and the de novo formation of hyaline-like cartilage and subchondral bone in the hMSC-treated knees. Furthermore, histological sectioning and staining of every sample confirmed regeneration of the full cartilage thickness and early subchondral bone repair, which was more similar to the native cartilage in the case of the cell-loaded ELR-based hydrogel. Overall histological differences between the two groups were assessed semi-quantitatively using the Wakitani scale and found to be statistically significant (p < 0.05). Immunofluorescence against a human mitochondrial antibody three months post-implantation showed that the hMSCs were integrated into the de novo formed tissue, thus suggesting their ability to overcome the interspecies barrier. Hence, we conclude that the use of xenogeneic MSCs embedded in an ELR-based hydrogel leads to the successful regeneration of hyaline cartilage in osteochondral lesions.

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

“…Media supplied with human platelet lysate from younger donors were able to facilitate MSC expansion and osteogenic differentiation[ 146 ]. Additionally, many bioactive hydrogels[ 147 ], biomimetic scaffolds[ 148 ], and other biomaterials[ 149 , 150 ] have been tested to assess whether they can modify aged MSCs. Removal of senescent cells in a high-throughput manner is another strategy that can be used to address the challenge of senescence[ 151 ]; this strategy, which has been explored in clinical trials, involves the isolation and enumeration of senescent MSCs from undiluted human whole blood.…”

An elastin-like recombinamer-based bioactive hydrogel embedded with mesenchymal stromal cells as an injectable scaffold for osteochondral repair

“…MSCs are available from different auto-, allo- and xenogeneic sources [16]. The first two options offer an immunologically safer approach, whereas the latter hugely increases the availability of MSCs [17]. Although there are several studies with successful results using xenogeneic MSCs in different animal hosts [18], only autologous [19] or allogenic cells [13] have been successfully used in humans, with negligible immunological response [20].…”

Biocompatibility of two model elastin‐like recombinamer‐based hydrogels formed through physical or chemical cross‐linking for various applications in tissue engineering and regenerative medicine

“…Herein, we aim to investigate the cytocompatibility and biocompatibility of two recently developed families of hydrogels based on elastin‐like recombinamers (ELRs) (Rodríguez‐Cabello, Martín, Alonso, Arias, & Testera, ), both of which are designed as a multipurpose approach for different TERM applications, such as bone (Coletta et al, ) and osteochondral regeneration (Pescador et al, ), or to improve the traceability of ELR‐based hydrogels through the recombinant conjugation of fluorescent proteins (Ibáñez‐Fonseca, Alonso, Arias, & Rodríguez‐Cabello, ), among others. ELRs are genetically engineered protein‐based materials whose composition is inspired by the primary sequence found in natural elastin, specifically the VPGXG pentapeptide, where X can be any amino acid except L‐proline.…”