From bench to clinic and back: skeletal stem cells and impaction bone grafting for regeneration of bone defects.

Tissue engineering offers enormous potential for bone regeneration. Despite extensive in vitro and in vivo work, few strategies translate into clinical practice. This paper describes the combination of skeletal stem cells (SSCs) and impaction bone grafting (IBG) for the treatment of patients with bone defects associated with avascular necrosis of the femoral head. SSCs and milled allograft were impacted into necrotic bone in the femoral heads of four patients. Three patients remained asymptomatic at 22-44 month follow-up, but one patient has required total hip replacement (both hips). This has allowed retrieval of the femoral heads, which were analysed structurally and functionally by µCT, histology and mechanical testing. A central channel of impacted bone was found in the femoral heads, which displayed a mature trabecular micro-architecture. The impacted bone was denser than the surrounding trabecular bone, as strong in compression and with histological micro-architecture comparable to that of trabecular bone. Analysis of the retrieved femoral head samples has demonstrated that this tissue-engineering strategy regenerates bone that is both structurally and functionally analogous to normal trabecular bone. SSCs, together with IBG, have proved an effective treatment for avascular necrosis of the femoral head and offer significant potential for the broader spectrum of bone defects.

A tissue engineering strategy for the treatment of avascular necrosis of the femoral head.

BACKGROUND & PURPOSE: Skeletal stem cells (SSCs) and impaction bone grafting (IBG) can be combined to produce a mechanically stable living bone composite. This novel strategy has been translated to the treatment of avascular necrosis of the femoral head. Surgical technique, clinical follow-up and retrieval analysis data of this translational case series is presented. METHODS: SSCs and milled allograft were impacted into necrotic bone in five femoral heads of four patients. Cell viability was confirmed by parallel in vitro culture of the cell-graft constructs. Patient follow-up was by serial clinical and radiological examination. Tissue engineered bone was retrieved from two retrieved femoral heads and was analysed by histology, microcomputed tomography (µCT) and mechanical testing. RESULTS: Three patients remain asymptomatic at 22- to 44-month follow-up. One patient (both hips) required total hip replacement due to widespread residual necrosis. Retrieved tissue engineered bone demonstrated a mature trabecular micro-architecture histologically and on µCT. Bone density and axial compression strength were comparable to trabecular bone. CONCLUSIONS: Clinical follow-up shows this to be an effective new treatment for focal early stage avascular necrosis of the femoral head. Unique retrieval analysis of clinically translated tissue engineered bone has demonstrated regeneration of tissue that is both structurally and functionally analogous to normal trabecular bone.

Skeletal stem cells and bone regeneration: translational strategies from bench to clinic.

Clinical imperatives for new bone to replace or restore the function of traumatized or bone lost as a consequence of age or disease has led to the need for therapies or procedures to generate bone for skeletal applications. Tissue regeneration promises to deliver specifiable replacement tissues and the prospect of efficacious alternative therapies for orthopaedic applications such as non-union fractures, healing of critical sized segmental defects and regeneration of articular cartilage in degenerative joint diseases. In this paper we review the current understanding of the continuum of cell development from skeletal stem cells, osteoprogenitors through to mature osteoblasts and the role of the matrix microenvironment, vasculature and factors that control their fate and plasticity in skeletal regeneration. Critically, this review addresses in vitro and in vivo models to investigate laboratory and clinical based strategies for the development of new technologies for skeletal repair and the key translational points to clinical success. The application of developmental paradigms of musculoskeletal tissue formation specifically, understanding developmental biology of bone formation particularly in the adult context of injury and disease will, we propose, offer new insights into skeletal cell biology and tissue regeneration allowing for the critical integration of stem cell science, tissue engineering and clinical applications. Such interdisciplinary, iterative approaches will be critical in taking patient aspirations to clinical reality.