Tendon to bone insertion site injuries are a leading cause of pain and disability in elderly as well as young populations. At the rotator cuff, where there are no repair techniques that are immune from recurrent tears, short to mid term failure rates have been reported to be as high as 94%. Similarly, flexor tendon insertion site repairs do not heal well. The two key features of the failed healing response are loss of bone mineral density and lack of fibrocartilage formation at the interface. Therefore,the overall objective of this study is to use bioengineering approaches to promote bone and fibrocartilage formation in order to improve the tendon to bone repair. Our tissue engineering approach will use the fetal development of tendon to bone insertions as motivation for promoting a regenerative healing response in our two well established animal models. Specifically, the expression of bone morphogenetic protein 2 (BMP-2) and bone morphogenetic protein 12 (BMP-12) will be upregulated to promote the formation of bone and fibrocartilage, respectively. BMP-2 has been implicated in bone fetal development and has successfully been used to promote bone formation in adult tissues. BMP-12 has been implicated in joint fetal development and has been demonstrated to induce neo-tendon/fibrocartilage formation when implanted subcutaneously. In this study, autologous mesenchymal stem cells will be transformed to produce the factors of interest and delivered using a collagen matrix. The mechanical loading environment has also been implicated in the development and maintenance of bone. Fetal development and adult healing studies have demonstrated that increased loading results in the formation of bone, while decreased loading results in the resorption of bone. The role of mechanical loading during healing will be explored by removing the loading across the repair site in one group and enhancing the loading across the repair site in a second group.
In specific aim 1 we will stimulate osteoblasts to produce bone at the healing canine flexor tendon- bone insertion site through biologic (i.e., BMP-2) and mechanical (i.e., increased loading) means.
In specific aim 2 we will develop biomechanical models to predict the stresses at the tendon to bone interface.
In specific aim 3 we will stimulate repair site cells to produce fibrocartilage at the healing rat supraspinatu tendon-bone insertion through biologic (i.e., BMP-12) means. The long term goal of our research program is to provide therapeutic solutions to the clinical problem of tendon to bone healing. The candidate's expertise in bioengineering will be combined with the mentors strengths in clinical science and molecular biology to form a unique and well balanced interdisciplinary team.
|Thomopoulos, Stavros; Kim, H Mike; Silva, Matthew J et al. (2012) Effect of bone morphogenetic protein 2 on tendon-to-bone healing in a canine flexor tendon model. J Orthop Res 30:1702-9|
|Liu, Y X; Thomopoulos, S; Birman, V et al. (2012) Bi-material attachment through a compliant interfacial system at the tendon-to-bone insertion site. Mech Mater 44:|
|Liu, Yanxin; Birman, Victor; Chen, Changqing et al. (2011) Mechanisms of Bimaterial Attachment at the Interface of Tendon to Bone. J Eng Mater Technol 133:|
|Thomopoulos, Stavros; Das, Rosalina; Birman, Victor et al. (2011) Fibrocartilage tissue engineering: the role of the stress environment on cell morphology and matrix expression. Tissue Eng Part A 17:1039-53|
|Kim, H Mike; Nelson, Gregory; Thomopoulos, Stavros et al. (2010) Technical and biological modifications for enhanced flexor tendon repair. J Hand Surg Am 35:1031-7; quiz 1038|
|Thomopoulos, S; Genin, G M; Galatz, L M (2010) The development and morphogenesis of the tendon-to-bone insertion - what development can teach us about healing -. J Musculoskelet Neuronal Interact 10:35-45|
|Fomovsky, Gregory M; Thomopoulos, Stavros; Holmes, Jeffrey W (2010) Contribution of extracellular matrix to the mechanical properties of the heart. J Mol Cell Cardiol 48:490-6|
|Genin, Guy M; Kent, Alistair; Birman, Victor et al. (2009) Functional grading of mineral and collagen in the attachment of tendon to bone. Biophys J 97:976-85|
|Thomopoulos, Stavros; Zampiakis, Emmanouil; Das, Rosalina et al. (2008) The effect of muscle loading on flexor tendon-to-bone healing in a canine model. J Orthop Res 26:1611-7|
|Wopenka, Brigitte; Kent, Alistair; Pasteris, Jill D et al. (2008) The tendon-to-bone transition of the rotator cuff: a preliminary Raman spectroscopic study documenting the gradual mineralization across the insertion in rat tissue samples. Appl Spectrosc 62:1285-94|