Skeletal defects resulting from trauma, tumors, or abnormal development frequently require surgical treatment to restore normal tissue function. To overcome the limitations associated with conventional surgical treatments, several tissue engineering approaches have been developed. In particular, the use of scaffolds enriched with stem cells appears to be a very promising strategy. A crucial issue in this approach is how to control stem cell behavior. In this respect, the effects of growth factors, scaffold surface characteristics, and external 'active' loading conditions on stem cell behavior have been investigated. Recently, it has become clear that the stiffness of a scaffold is a highly potent regulator of stem cell differentiation. In addition, the stiffness of a scaffold affects cell migration, which is important for the infiltration of host tissue cells. This review summarizes current knowledge on the role of the scaffold stiffness in the regulation of cell behavior. Furthermore, we discuss how this knowledge can be incorporated in scaffold design which may provide new opportunities in the context of orthopedic tissue engineering.

Histologically, two types of bone reconstruction are distinguished: modeling and remodeling. Modeling changes the amount of bone and determines its geometrical form in relation to the prevailing mechanical loads and their resulting deformation (strain). Remodeling renews existing bone in a sequence of resorption and formation. However, in both processes the cells responsible for resorption and formation are the same: osteoclasts and osteoblasts. We studied if there is a relation between the activity of these cells and the deformation of the local bone tissue during remodeling. Two finite element models were built on a microscopic, supracellular level: (1) a secondary osteon in cortical bone and (2) a Howship's lacuna in a trabecula. Both models were loaded in the ''natural,'' that is, longitudinal direction. Equivalent strains were determined as a measure for the deformation of the bone tissue. In the first model, the strain field around the osteon showed a region of decreased deformation in front of the tunnel, just where osteoclasts excavate cortical bone tissue. Behind the cutting cone, elevated strain levels appear in the tunnel wall at locations where osteoblasts are active. The second model showed that a local excavation of a loaded trabecula leads to higher strains at the bottom of the lacuna, where resorption is stopped and osteoblasts are recruited to refill the gap. However, in the direction of loading reduced strain levels appear, just where resorption continues to proceed along the trabecular surface. We conclude that at the tissue level, strain distributions occur during the remodeling process that show a relationship to the activity of osteoblasts and osteoclasts. This suggests that BMU coupling, that is, the subsequent activation of osteoclasts and osteoblasts during remodeling, is a strain-regulated phenomenon. (J Bone Miner Res 2000;15: 301-307)

Regenerative therapies offer attractive alternatives for the treatment of osteochondral defects. Adipose-derived stromal vascular fraction (SVF) cells allow the development of one-step surgical procedures by their abundant availability and high frequency. In this pilot study we evaluated the in vivo safety, feasibility, and efficacy of this concept using scaffolds seeded with freshly isolated (SVF) or cultured adipose stem cells (ASCs), and compared these to their acellular counterparts. Osteochondral defects were created in medial condyles and trochlear grooves in knees of eight goats. Defects were filled with acellular collagen I/III scaffolds or scaffolds seeded with SVF cells or cultured ASCs. Osteochondral regeneration was evaluated after 1 and 4 months by macroscopy, immunohistochemistry, biomechanical analysis, microCT analysis, and biochemistry. After 1 month, no adverse effects were noted. Microscopic, but not macroscopic evaluation showed considerable yet not significant differences, with cell-loaded constructs showing more extensive regeneration. After 4 months, acellular constructs displayed increased regeneration, however, to a lesser degree than cell-treated constructs. The latter exhibited more extensive collagen type II, hyaline-like cartilage, and higher elastic moduli, and their glycosaminoglycan content in the cartilaginous layer better approached native tissue values. Moreover, their defect regions contained higher levels of regenerated, mature subchondral bone with more intense collagen type I staining. SVF cells tended to perform best on all parameters. In summary, this pilot study demonstrated the preclinical safety and feasibility of a one-step surgical procedure for osteochondral defect regeneration. Similar regeneration was found between freshly isolated SVF cells and cultured ASCs. Larger studies with longer follow-up are required to substantiate these findings.

Intervertebral disc degeneration describes the vicious cycle of the deterioration of intervertebral discs and can eventually result in degenerative disc disease (DDD), which is accompanied by low‐back pain, the musculoskeletal disorder with the largest socioeconomic impact world‐wide. In more severe stages, intervertebral disc degeneration is accompanied by loss of joint space, subchondral sclerosis, and osteophytes, similar to osteoarthritis (OA) in the articular joint. Inspired by this resemblance, we investigated the analogy between human intervertebral discs and articular joints. Although embryonic origin and anatomy suggest substantial differences between the two types of joint, some features of cell physiology and extracellular matrix in the nucleus pulposus and articular cartilage share numerous parallels. Moreover, there are great similarities in the response to mechanical loading and the matrix‐degrading factors involved in the cascade of degeneration in both tissues. This suggests that the local environment of the cell is more important to its behavior than embryonic origin. Nevertheless, OA is widely regarded as a true disease, while intervertebral disc degeneration is often regarded as a radiological finding and DDD is undervalued as a cause of chronic low‐back pain by clinicians, patients and society. Emphasizing the similarities rather than the differences between the two diseases may create more awareness in the clinic, improve diagnostics in DDD, and provide cross‐fertilization of clinicians and scientists involved in both intervertebral disc degeneration and OA.