Autologous engineering of cartilage

Abstract

Treatment of full-thickness damage to hyaline cartilage is hampered by the limited availability of autologous healthy cartilage and the lengthy, cost-prohibitive cell isolation and expansion steps associated with autologous cartilage implantation (ACI). Here we report a strategy for de novo engineering of ectopic autologous cartilage (EAC) within the subperiosteal space (in vivo bioreactor), through the mere introduction of a biocompatible gel that might promote hypoxia-mediated chondrogenesis, thereby effectively overcoming the aforementioned limitations. The EAC is obtained within 3 wk post injection of the gel, and can be press-fit into an osteochondral defect where it undergoes remodeling with good lateral and subchondral integration. The implanted EAC showed no calcification even after 9 mo and attained an average O'Driscoll score of 11 (versus 4 for controls). An "on demand" autologous source of autologous cartilage with remodeling capacity is expected to significantly impact the clinical options in repair of trauma to articular cartilage.A nnually, in the United States alone over 1 million individuals, are treated for lesions in articular cartilage with over 250,000 patients requiring knee arthroscopy (1). Damage to hyaline cartilage often precedes osteoarthritis (2). Among cartilage lesions, osteochondritis dissecans (OCD), which involves full-thickness damage to the hyaline cartilage and underlying bone (3), is being diagnosed with an increasing frequency. While OCD is most often diagnosed in the knee, it may also affect other joints such as ankle, elbow, and shoulder (3). OCD is clinically challenging to treat as it is multifactorial and, furthermore, treatment is hampered by the limited self-repair potential of hyaline cartilage that is due to the absence of resident pluripotent cells and the lack of vasculature and lymphatics (4, 5). Notwithstanding, hyaline cartilage is key to successful repair as its unique cellular organization and extra cellular matrix composition confers load bearing and lubricious properties to the joint surface. Currently, injury to the articular cartilage surface, including OCD lesions, is treated by either physiotherapy, stimulation of regeneration by arthroscopic drilling, autologous osteochondral plugs from non-weight bearing regions, or injection of cells under a periosteal flap (ACI) (5, 6). Whereas the best treatment for cartilage lesions remains to be defined, ACI, in spite of its suboptimal outcomes (i.e., formation of undesirable fibrocartilage, poor, integration, and calcification), along with engineered cartilage and osteochondral tissue constructs, are promising as treatment options (7, 8) However, the clinical implementation of ACI and engineered constructs is hampered by the costs and logistics involved with isolation and expansion of cells and variability in quality of the engineered tissue. We recently proposed a unique paradigm for de novo engineering of tissues, the in vivo bioreactor (IVB), in which a woundhealing response provoked within a confined subperi...

Mechanically Tunable Bioink for 3D Bioprinting of Human Cells

“…[5] However, formulating these materials with specific mechanical properties for 3D printing requires both optimization of the formulation and the 3D printing parameters. Agarose, a polysaccharide that undergoes thermally reversible gelation and is stable under physiological conditions, has been explored in cartilage repair, [19] as an injectable tissue filler, [20] and synthetic 3D cell matrix. [21] More recently, agarose has been explored as a bioink for the 3D printing of umbilical artery endothelial cells; [22] however, tailoring mechanical properties of agarose gels requires changing the concentration of agarose and this profoundly impacts its rheological behavior, thus limiting its utilization as a mechanically tunable bioink.…”

Cartilage Tissue Engineering; Lessons Learned From Periosteum

“…The hypercellular cartilage induced within the IVB, was harvested during its early chondrogenic phase and successfully implanted into an osteochondral defect where excellent lateral integration into the subchondral bone as well as in the articular cartilage was observed. Importantly, absence of ossification of the transplanted ectopically produced cartilage was observed in a long term followup study [48].…”

“…They also went on to demonstrate chondrogenesis within the IVB by the injection of a hyaluronic acid-based gel containing the anti-angiogenic factor Suramin. In this system the inhibition of angiogenesis provided the hypoxic character to the biogel-environment which was likely to favour the formation of cartilage that resembles early fracture callus [48,49]. Following the initial report, which focused on bone, we aimed to achieve controlled chondrogenesis within the IVB and control the local subperiosteal environment by simply injecting a gel to initiate the endochondral process.…”

“…Scotti et al [50] showed that if early non-hypertrophic endochondral tissue is harvested and implanted the transplanted graft would not further ossify [50]. As such it seems that in contrast to transplant periosteum directly after harvesting, ossification of repaired cartilage does not occur when periosteum is differentiated into cartilage prior to transplantation [46][47][48].…”

Delivering regeneration

“…The translation from "bench to bedside" requires significant input from the clinicians with respect to adaptation of prevailing standards in surgical intervention to the development of new biomaterials. A good example of such a collaborative approach is the in vivo bioreactor paradigm [13,14]. In the in vivo bioreactor paradigm, the de novo formation of a fully functional bone or cartilage is invoked and controlled purely through the minimally invasive placement of a biomaterial with precise physicochemical characteristics.…”