Microsphere-Based Gradient Implants for Osteochondral Regeneration: a Long-Term Study in Sheep

Abstract

Background:The microfracture technique for cartilage repair has limited ability to regenerate hyaline cartilage. Aim: The current study made a direct comparison between microfracture and an osteochondral approach with microsphere-based gradient plugs. Materials & methods: The PLGA-based scaffolds had opposing gradients of chondroitin sulfate and β-tricalcium phosphate. A 1-year repair study in sheep was conducted. Results: The repair tissues in the microfracture were mostly fibrous and had scattered fissures with degenerative changes. Cartilage regenerated with the gradient plugs had equal or superior mechanical properties; had lacunated cells and stable matrix as in hyaline cartilage. Conclusion: This first report of gradient scaffolds in a long-term, large animal, osteochondral defect demonstrated potential for equal or better cartilage repair than microfracture.

Material characterization of microsphere-based scaffolds with encapsulated raw materials

“…The gradient capability that we have demonstrated with microsphere-based scaffolds allows for CS and TCP to be encapsulated in opposing gradients within a single biomaterial construct [8, 14]. We have a preliminary understanding of the mechanics and the raw material retention within these scaffolds over the crucial first month, from which we can infer gradients not only in initial material composition, but also in mechanics and degradation and release rate.…”

“…Monodisperse microspheres [10] were prepared according to our previously reported technology [8, 11-14]. Briefly, the polymer stream was broken into uniform polymer droplets by exposing the stream to acoustic excitation.…”

“…Particularly, the changes in the degradation rate in the first month impacts the initial cellular differentiation and sets the stage for downstream regeneration processes. In view of the imminent translational applications, we chose the polymer formulation that was employed in a Coulter Foundation-funded sheep study [8] and input from regulatory consultants.…”

Microsphere-based scaffolds encapsulating tricalcium phosphate and hydroxyapatite for bone regeneration

“…The net ceramic content encapsulated in TCP/HAp 7:3 and TCP/HAp 1:1 groups was 30 wt%. Using the PLGA-protein and PLGA-TCP/HAp emulsions, microspheres with mean diameters ranging from 172–186 µm (Supplementary Figure 1), were fabricated via our previously reported technology [32, 21, 33, 22, 23, 27, 34, 24, 35, 28, 25, 26, 36–38]. Briefly, using acoustic excitation produced by an ultrasonic transducer (Branson Ultrasonics, Danbury, CT), regular jet instabilities were created in the polymer stream, thereby creating uniform polymer droplets.…”

“…Our group has demonstrated that microsphere-based scaffolds can provide opposing signal gradients via spatio-temporal release of growth factors to facilitate regeneration of complex tissues such as the osteochondral interface [21–26]. Furthermore, we have shown that opposing gradients of materials such as TCP and chondroitin sulfate can provide raw materials (i.e., bioactive signals and building blocks) to simultaneously guide the regional osteo- and chondrogenic differentiation of cells [27, 28]. Delivering raw materials in lieu of growth factors holds tremendous financial incentive for translation to the clinic by providing a more streamlined path for regulatory approval as well as saving on the cost of including the growth factor in the product.…”