No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing.

Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain.

Determination of joint loads using new sensate scaffolds for regenerating large cartilage defects in the knee.

Two complete unicondylar surface replacement scaffold designs to support tissue-engineered cartilage growth that utilized adult endogenous stem cells were 3D printed and tested in a dog stifle model. Integrated rosette strain gauges were calibrated and used to determine shear loading within stifle joints for up to 12 months. An activity index that compared extent of daily activity with tissue formation showed differences in the extent and quality of new tissue with the most active animal having the most new tissue formation. Shear loads were highest early and decreased with time indicating that cartilage tissue formation begins while tissues experience high shear loads and continues as the loads decrease toward normal physiological levels. Scaffolds with biomimetic support pegs facilitated the most rapid bone ingrowth and were noted to have more cartilage formation with better quality cartilage as measured using both indentation testing and histology. Comparison of implant placement depth to previous studies suggested that placement depth affects the amount of tissue formation. This study provides measurements of loading patterns and cartilage regeneration on a complete medial condylar surface replacement that can be used for preclinical testing of a tissue engineering approach for the most common form of early stage osteoarthritis, unicondylar disease. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1409-1421, 2017.