Nature Materials | Commentary Biomaterials in the repair of sports injuries
Journal name:Nature Materials Volume:11, Pages: 652–654 Year published: (2012) DOI: doi:10.1038/nmat3392 Published online 24 July 2012
The optimal stimulation of tissue regeneration in bone, cartilage and spinal cord injuries involves a judicious selection of biomaterials with tailored chemical compositions, micro- and nanostructures, porosities and kinetic release properties for the delivery of relevant biologically active molecules.
The same principle, namely the use of materials for reimplanting cells and for guiding and stimulating healing responses, is applied to addressing spinal cord injuries. Horseback riding and diving accidents can cause devastating spinal cord injuries, for which there is still no solution. Paraplegic and quadriplegic patients are wheelchair bound. Although Herculean efforts at rehabilitation can return some function, the secondary morbidities associated with loss of muscle function and motoric ability can cause death, which is what happened to the actor Christopher Reeve. Minimization and control of the inflammatory response as soon as possible following the severance of the nerve conduits is an important contributor to the potential of healing. But healing essentially depends on the nerve conduits being recreated; without bridging the gap in the severed spinal cord, motoric function is not restored.
Because of the unique nature of spinal cord injuries, experimental successes have lagged far behind the development of biomaterials for other sports-related injuries. At present there are no clinical options to repair the spinal cord. The predominant feature of spinal cord injury is damage to long nerve-fibre (or axon) tracts, resulting in loss of communication between the brain and the body. As such, the challenge for spinal cord repair is not simply to fill in a lesion with a new cellular matrix, but to recapitulate the highly organized axon pathways that were lost16. Several strategies in development provide biomaterial guides, such as directional micro- and nanostructures on materials’ surfaces aimed at coaxing disconnected axons to regrow across spinal cord lesions17, 18, 19, 20. However, scarring of glial tissue that walls off the margins of spinal cord lesions can physically block axon penetration, and the central nervous system continuously generates multiple factors that inhibit axon growth16, 17, 18, 19, 20, 21, 22. Moreover, ongoing inflammation and loss of myelin — the insulating layer wrapping axons — pose additional hurdles16, 17, 18, 19, 20, 21, 22. These observations have led to approaches that incorporate combinations of directional biomaterials, biochemical factors and cells. For example, hydrogels with graded stiffness and/or linearly oriented fibres or nanostructures have been proposed to promote growth and provide a physical guide21, 22, 23. These materials can also be doped with graded concentrations of nourishing (trophic) factors to promote growth, with neutralizing antibodies and modulators of signal-transduction pathways to reduce inhibition of axon growth, with anti-inflammation therapies, and/or with the use of proteases (such as chondroitinase ABC) that can break down glial scars16, 17, 24, 25, 26, 27. Furthermore, these biochemicals can be incorporated in slow-release compositions for long-term effects26, 27.
Hydrogels consisting of dissociated cells28 or engineered nervous tissue as part of a transplantable nervous-tissue construct composed of stretch-grown long axon tracts spanning populations of neurons29, 30 (Fig. 3) have also been used in cell therapy. Notably, the nervous tissue constructs have shown early promise as living scaffolds to guide axon regeneration across spinal cord lesions31. However, whereas a cell-based therapy using engineered remyelinating cells seemed useful in preclinical models, a recent clinical trial using human embryonic stem cells injected into the injured spinal cord failed to show benefit in a small number of patients32. Overall, whereas there has been much progress in developing strategies to repair spinal cord injuries, an optimal approach has yet to be identified.
The transplantable nervous-tissue constructs are composed of stretch-grown long axon tracts (two tracts composed of thousands of axons are shown in green) spanning two populations of neurons. To initiate stretch growth, two adjacent populations of neurons connected by axons are separated from each other at accelerating rates using a programmed microstepper motor system. The resulting continuous mechanical tension on the spanning axons induces rapid stretch growth. Once the axons are grown to a desired length, the engineered nervous tissue is embedded in a hydrogel, which provides stability for transplant into spinal cord lesions. The axon tracts are ~50 μm in width. I
Although much progress has been made in using materials to harness the body’s innate healing response, ideal treatments or just simply satisfactory treatments do not exist yet. As such, the quest for biomaterials that optimally affect cellular function and tissue formation continues with an ever-refined, judicious selection of chemical compositions, porosities and kinetic release properties for the delivery of growth factors and other relevant biologically active molecules. Although this represents the overarching principle, there are numerous details that differ from tissue to tissue and from condition to condition. Moreover, other parameters such as stress state and extent of injury play a role. Nevertheless, the use of biomaterials for treating sports injuries is a mainstay, providing improved patient outcomes in a number of disabling scenarios.