Connective tissues such as tendons or ligaments attach to bone across a multitissue interface with spatial gradients in composition, structure, and mechanical properties. These gradients minimize stress concentrations and mediate load transfer between the soft and hard tissues. Given the high incidence of tendon and ligament injuries and the lack of integrative solutions for their repair, interface regeneration remains a significant clinical challenge. This review begins with a description of the developmental processes and the resultant structure-function relationships that translate into the functional grading necessary for stress transfer between soft tissue and bone. It then discusses the interface healing response, with a focus on the influence of mechanical loading and the role of cell-cell interactions. The review continues with a description of current efforts in interface tissue engineering, highlighting key strategies for the regeneration of the soft tissue–to-bone interface, and concludes with a summary of challenges and future directions.

/pdf/functional-attachment-of-soft-tissues-to-bone-development-2cfgu0cby6.pdf

Functional attachment of soft tissues to bone: development, healing, and tissue engineering.

The attachment of dissimilar materials is a major challenge because of the high levels of stress that develop at such interfaces. An effective solution to this problem develops at the attachment of tendon (a compliant “soft tissue”) to bone (a stiff “hard tissue”). This tissue, the “enthesis”, transitions from tendon to bone through gradations in structure, composition, and mechanical properties. These gradations are not regenerated during tendon-to-bone healing, leading to a high incidence of failure after surgical repair. Understanding the development of the enthesis may allow scientists to develop treatments that regenerate the natural tendon-to-bone insertion. Recent work has demonstrated that both biologic and mechanical factors drive the development and morphogenesis of the enthesis. A cascade of biologic signals similar to those seen in the growth plate promotes mineralization of cartilage on the bony end of the enthesis and the formation of fibrocartilage on the tendon end of the enthesis. Mechanical loading is also necessary for the development of the enthesis. Removal of muscle load impairs the formation of bone, fibrocartilage, and tendon at the developing enthesis. This paper reviews recent work on the development of the enthesis, with an emphasis on the roles of biologic and mechanical factors.

The development and morphogenesis of the tendon-to-bone insertion - what development can teach us about healing -.

Publisher Summary This chapter describes the dynamic characteristic of tendon––the ability of a tendon to modulate its structural and material properties to meet mechanical requirements distinct from the usual need for strength in tension Tendon performs the mechanical role of transmitting the tensional force generated by contraction of its muscle of origin to the bone upon which it inserts The histology, biochemistry, and cell biology of regions of the flexor digitorum profundus tendon (deep digital flexor tendon) either subjected to tension or to compression are described in the chapter The hypothesis that tendon fibroblasts and the extracellular matrix they produce are modulated according to their mechanical requirements is explored The development of cartilaginous tissue in the region of tendon subjected to compressive forces is genetically programmed The stimulus to produce large Proteoglycan (PG) is generated by one or more soluble factors that are released under defined conditions and carried systemically to a population of target cells Many fibroblasts in adult tissue have the capacity to generate a cartilage like tissue

Structural specialization in tendons under compression.

More than 300 primary cilia have been identified electronmicroscopically in a variety of embryonic and mature connective tissue cells. To further define the enigmatic function of these cilia, we examined the interrelationships between the basal apparatus and cytoplasmic organelles and the ciliary shaft and the extracellular matrix. The basal diplosome was consistently associated with the secretory organelles including the maturing face of the Golgi complex, Golgi vacuoles and vesicles, the microtubular network, the plasma membrane, and coated pits and vesicles. Small vesicles and amorphous granules were also observed within the ciliary lumen and adjacent to the ciliary membrane. Microtubule-membrane bridges linked axonemal tubules to the ciliary membrane. The position, projection, and orientation of the axoneme were influenced by the structural organisation and mechanical properties of the matrix and frequently caused angulation of the ciliary shaft relative to the basal body. Located midway between the secretory apparatus and the extracellular matrix, primary cilia would appear ideally situated to mediate the necessary interaction between the cell and its surrounding environment prerequisite to the formation and maintenance of a functionally effective matrix. We propose that primary cilia in connective tissue cells could act as multifunctional, cellular cybernetic probes, receiving, transducing, and conducting a variety of extrinsic stimuli to the intracellular organelles responsible for effecting the appropriate homeostatic feedback response to changes in the extracellular micro-environment.

Analysis of the morphology and function of primary cilia in connective tissues:A cellular cybernetic probe?

Effect of stress deprivation and cyclic tensile loading on the material and morphologic properties of canine flexor digitorum profundus tendon: An in vitro study

Digital flexor tendons isolated from 17–18 day embryonic chickens were cultured intact, either on steel mesh grids, or in an apparatus designed to apply a mechanical load to the tissue. Tendons cultured without an applied load continued to synthesize protein and glycosaminoglycans throughout a 7-day period, but DNA synthesis decreased during this time. Increases in both protein and DNA synthesis were observed in tendons experimentally loaded for 48–72 h.Glycosaminoglycan production by tendons isolated from 17-day embryos was also increased in loaded tendons, sulfated GAG being increased more than hyaluronic acid. The same loading regime applied to tendons from 18-day embryos produced a smaller, yet significant increase in sulfated glycosaminoglycans but hyaluronate production was reduced.These investigations demonstrate that embryonic chicken tendons can be maintained in a viable state in organ culture and may provide a useful model for studies of the effects of mechanical forces on the synthetic capabili...

The Effect of Tensional Load on Isolated Embryonic Chick Tendons in Organ Culture

Glycosaminoglycan synthesis by cells cultured from nodule or band tissues of patients with Dupuytren's disease was compared with that of skin fibroblasts cultured from uninvolved areas of the palm. No differences were observed in culture which could account either for the abnormal glycosaminoglycan content or the increased cellularity of the diseased tissues. It is suggested that the behavior of Dupuytren's cells in vivo may result from a response to local conditions within the palm rather than from the expression of an irreversible change in their glycosaminoglycan metabolism.

B. M. Thompson

Papers

The Effect of Tensional Load on Isolated Embryonic Chick Tendons in Organ Culture

Glycosaminoglycan Synthesis by Dupuytren's Cells in Culture