# Engineered and decellularized human cartilage graft exhibits intrinsic immunosuppressive properties and full skeletal repair capacity

## TL;DR

Engineered and decellularized human cartilage grafts can safely repair bone defects and suppress immune reactions, showing promise for future clinical use.

## Contribution

Demonstrates that decellularized human cartilage grafts retain healing properties and exhibit immunosuppressive effects in preclinical models.

## Key findings

- Decellularized human cartilage grafts repaired critical-sized bone defects in rats.
- Grafts suppressed immune responses by controlling macrophage and T cell activity.
- Cartilage grafts preserved osteoinductive properties after decellularization.

## Abstract

Tissue engineering creates living substitutes to repair damaged body parts. Patient-specific methods can be costly, slow, and unreliable. A better approach uses special cell lines to produce tissue grafts. After removing the cells, the remaining structure and growth signals help the body heal naturally. This method was tested using a custom cell line to create human cartilage, which showed strong bone-healing ability. For clinical translation, key challenges include proper cell removal, reducing immune reactions, and proving effectiveness. Our study successfully engineered and removed cells from human cartilage while keeping its healing properties. In rats, these grafts repaired bone defects, showing their potential for safe and effective use in future human trials.

Tissue engineering strategies predominantly consist of the autologous generation of living substitutes capable of restoring damaged body parts. Persisting challenges with patient-specific approaches include inconsistent performance, high costs, and delayed graft availability. Toward developing a one-for-all solution, a more attractive paradigm lies in the exploitation of dedicated cell lines for the fabrication of human tissue grafts. Following decellularization, this new class of biomaterials relies on the sole extracellular matrix and embedded growth factors instructing endogenous repair. This conceptual approach was previously validated using a custom mesenchymal cell line for the manufacturing of human cartilage, exhibiting remarkable osteoinductive capacity following lyophilization. Key missing criteria to envision clinical translation include proper decellularization as well as stringent assessment of both immunogenicity and regenerative performance. Here, we report the engineering and subsequent decellularization of human cartilage tissue with minimal matrix impairment. Ectopic evaluation in immunocompetent (IC) and immunocompromised animals reveals preservation of osteoinductivity predicted by macrophage kinetic of polarization. By establishing in vitro human allogeneic coculture models, we evidenced the immunosuppressive properties of cell-free human cartilages, controlling macrophage and dendritic cell maturation as well as T cell activation. Finally, regenerative performance was stringently assessed in an IC rat orthotopic model whereby decellularized human cartilage grafts achieved morphological and mechanical restoration of all critical-sized femoral defects. Taken together, our study provides robust safety and efficacy prerequisites prompting a first-in-human trial for engineered and decellularized human tissue grafts.