Assessment of stem cell carriers for tendon tissue engineering in pre-clinical models

Abbah et al. Stem Cell Research & Therapy 2014, 5:38 http://stemcellres.com/content/5/2/38 REVIEW Assessment of stem cell carriers for tendon tissue engineering in pre-clinical models Sunny Akogwu Abbah1, Kyriakos Spanoudes1, Timothy O’Brien2, Abhay Pandit1 and Dimitrios I Zeugolis1* Abstract Tendon injuries are prevalent and problematic, especially among young and otherwise healthy individuals. The inherently slow innate healing process combined with the inevitable scar tissue formation compromise functional recovery, imposing the need for the development of therapeutic strategies. The limited number of low activity/reparative capacity tendonresident cells has directed substantial research efforts towards the exploration of the therapeutic potential of various stem cells in tendon injuries and pathophysiologies. Severe injuries require the use of a stem cell carrier to enable cell localisation at the defect site. The present study describes advancements that injectable carriers, tissue grafts, anisotropically orientated biomaterials, and cell-sheets have achieved in preclinical models as stem cell carriers for tendon repair. Introduction Large tendon injuries that necessitate surgical intervention are of significant concern not only among athletes, but also in the general population. These injuries are often associated with prolonged disabilities that require long treatments and painful rehabilitation periods. Functional recovery is often incomplete, leaving the patient with life-long joint instability, which frequently result in arthritis [1]. Expectedly, this has serious social and economic implications. Specifically, an estimated 30 million cases of tendon and ligament injuries are seen worldwide annually, leading to extensive loss of man-hours [2]. The annual USA expenditure is estimated at US$30 billion, whilst European healthcare expenditure exceeds €115 billion per year [3,4]. The increasing return of people to various rigorous sporting activities after decades of * Correspondence: 1 Network of Excellence for Functional Biomaterials (NFB), Bioscience Building, National University of Ireland Galway (NUI Galway), Galway, Ireland Full list of author information is available at the end of the article sedentary lifestyle, coupled with the increasing life expectancy, is expected to further increase tendon injury incidents, putting a further financial strain on healthcare systems [5]. The limited number of low activity/reparative capacity resident cells in tendon tissues has been postulated to be the main culprit for the restricted regenerative capacity of tendon tissue [6-10]. Cell-based therapies promise to recapitulate essential biological processes of neonatal tendon development that would culminate in the regeneration of fully functional neo-tendon tissue. Indeed, cell-based tissue engineering strategies have witnessed a drift from an era focused primarily on feasibility studies to an era focused on optimisation and specific engineering of the implantable tissue constructs, appraised alongside therapeutic efficacy and safety [11-14]. This progress has come in parallel with increasing understanding of the intricate molecular mechanisms underlying the therapeutic potential of stem cells and their physical environment in different tissues [15-19]. Current evidence indicates that the therapeutic efficacy of stem cells relies heavily on their capacity to secrete a spectrum of bioactive/trophic molecules, with an extensive range of functions, including chemo-attraction, immunomodulation, angiogenesis, antiscarring and anti-apoptotic properties [20-22]. In a sense, this stem cell pool will act as a biological factory designed and built to function as a production line for progenitor cells and/or bioactive molecules, until differentiation towards the host tissue lineage occurs. It is therefore imperative to ensure optimal residency of viable and potent stem cells at the site of injury that will ultimately enable recapitulation of native cellularity back to normal, pre-injury levels. The major obstacles to direct cell injections are the localisation of the cell suspension at the target tissue, optimum timing of injection with respect to different healing stages, and maintenance of control over cell fate and functionality [23-26]. From a surgical perspective, stable fixation of any implanted graft is of paramount importance to avoid disruption under the dynamic © 2014 Abbah et al.; licensee BioMed Central Ltd. The licensee has exclusive rights to distribute this article, in any medium, for 12 months following its publication. After this time, the article is available under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abbah et al. Stem Cell Research & Therapy 2014, 5:38 http://stemcellres.com/content/5/2/38 mechanical environment native to the tendon. Although in equine patients anatomic characteristics and injury type preponderance [27,28] allow treatment of small defects in superficial digital flexor tendon with intratendinous injections, even with a small number (as low as 645,000) of bone marrow-derived mesenchymal stem cells (BMSCs) [29-31], the complexities of human tendon injuries often call for surgical debridement and implantation of a mechanically resilient three-dimensional scaffold that will sustain the mechanical loads of the local environment until definitive healing takes place. To this end, delivery of an appropriate cell population using injectable hydrogels, autologous, allogeneic or xenogeneic tissue grafts, anisotropically ordered biomaterials, or cell sheets, with localised and sustained delivery of bioactive/therapeutic molecule capacity (Figure 1), is at the forefront of academic, clinical and industrial investigation for tendon tissue engineering [32-37]. Here, we discuss the effectiveness demonstrated in tendon preclinical models of various stem cell populations and carrier systems. Page 2 of 9 Injectable stem cell carriers Minimally invasive injectable carriers, based on natural or synthetic polymers, are often utilised as carriers for localised and controlled release of cells along with bioactive/ therapeutic molecules in musculoskeletal repair. Such systems protect cell membranes from rupture during injection and facilitate prolonged cell survival and maintain cell functionality at the harsh injury environment, while the presence of functional moieties responsive to specific stimuli allow spatiotemporal release of their cargo, and the fast in situ self-assembly rate (<10 minutes) enables conformity with the injury site and direct integration with the host tissue [38-47]. Fibrin- and collagen-based hydrogels dominate in the tendon repair field. Both are naturally occurring materials characterised by low antigenicity and immunogenicity, and their inherent prop (...truncated)