Investigating biomechanical properties and structural changes post-stretch in neonatal brachial plexus

Virginia Guadalupe Orozco

doi:10.17918/00010850

The brachial plexus (BP) is an intricate network of nerves responsible for providing motor and sensory innervation to the upper extremities. A common neonatal BP nerve injury is neonatal brachial plexus palsy (NBPP), which occurs due to the overstretching of the BP during complicated birthing scenarios, such as shoulder dystocia. Despite improvements in obstetric care, NBPP continues to significantly impact infants' lives, with a worldwide incidence of 1 to 5 per 1,000 live births. While 70-90% of NBPP cases report spontaneous recovery, 30-40% resulted in permanently reduced range of motion, along with decreased strength, size, and girth of the affected upper extremity. The incidence of spontaneous recovery in NBPP is lower than previously expected, therefore increasing the need to improve preventative obstetric maneuvers to reduce neonatal BP injuries. Despite existing knowledge of BP biomechanical properties, a major limitation is the lack of available human neonatal BP data. Due to ethical constraints, no studies have reported the stretch-response of the human neonatal BP. Therefore, an alternative approach is to use a clinically relevant neonatal large animal model, such as a piglet model. Previous studies have demonstrated that mechanical stretch induce structural changes in peripheral nerves, with varying degrees of stretch leading to various levels of nerve tissue damage. Severe stretch injuries can cause irreversible nerve impairment, although not all stretch leads to permanent nerve dysfunction. Strain is a key factor in axonal injury, causing cytoskeletal alterations, axonal swelling, and impaired axonal transport, which can lead to neuronal dysfunction and degeneration. While studies have examined the impact of strain of peripheral nerves from adult humans and adult small animals, there is a lack of research on neonatal peripheral nerves, particularly structural changes associated with stretch. This gap is significant in understanding NBPP. The overall objective of this study was to characterize the neonatal BP biomechanical properties and corresponding structural changes subjected to stretch using a clinically relevant neonatal large animal model. To achieve this, the dissertation consisted of two specific aims. In the first specific aim the peak failure load and average strain at peak failure load were determined by performing in vivo failure tensile biomechanical tests on the neonatal BP using a neonatal piglet animal model. The average in vivo peak failure load and in vivo average strain at peak failure load of the neonatal BP complex was 15.3 ± 9.0 N and 36.4 ± 11.3%, respectively. Additionally, the in vivo average peak failure load, in vivo average strain at peak failure load, and diameter of each BP terminal nerve were reported. For the musculocutaneous nerve, the values were 6.5 ± 2.8 N, 36.8 ± 10.8%, and 0.09 ± 0.01 cm, respectively; for the ulnar nerve the values were 13.6 ± 3.5 N, 29.7 ± 4.8%, and 0.17 ± 0.02 cm; for the median nerve the values were 18.4 ± 4.8 N, 27.1 ± 8.3%, and 0.20 ± 0.02 cm; and for the radial nerve the values were 23.1 ± 8.4 N, 41.1 ± 9.5%, and 0.26 ± 0.04 cm. The average diameter of radial BP terminal nerve was significantly greater than the musculocutaneous and ulnar BP terminal nerves. The median BP terminal nerve average diameter was greater than the musculocutaneous BP terminal nerve. The in vivo average peak failure load of the musculocutaneous BP terminal nerve was significantly less than the median and radial BP terminal nerves. Additionally, it was determined that the in vivo average strain at peak failure of the radial BP terminal nerve was greater than the ulnar and median BP terminal nerves. The musculocutaneous BP terminal nerve in vivo average strain at peak failure load was significantly greater than the median BP terminal nerve. In the second specific aim the related structural changes, namely, vascular changes, fiber changes, and axoplasmic transport impairment, of the neonatal BP were examined at varying degrees of stretch using hematoxylin & eosin, neurofilament-immunofluorescence, and beta-amyloid precursor protein-immunofluorescence histological techniques, respectively. Each BP terminal nerve (musculocutaneous, median, ulnar, and radial) was stretched to pre-determined strain ranges (<10%, 10-20%, and >20%) corresponding to mild, moderate, and severe stretch groups, respectively. It was determined that vascular and nerve fiber changes and extent of fascicle changes and axoplasmic transport impairment of the neonatal BP were strain dependent. Using the modified scoring systems for vascular and nerve fiber changes, vascular and nerve fiber changes increased with increasing strain. All stretched BP terminal nerves (<10%, 10-20%, and >20%) significantly differed in the observed vascular and nerve fiber changes from the control samples that only underwent the surgical procedure. For all BP terminal nerves, the average nerve fiber score of the mild stretch group (<10% strain) was significantly less than the moderate (10-20% strain) and severe (>20% strain) stretch groups average nerve fiber score. Evaluating the extent of fascicle changes, demonstrated that nerve fiber area within the widest fascicle decreased with increasing strain. The extent of axoplasmic transport impairment was measured by the accumulation of beta-amyloid precursor protein ([beta]APP) at the site of injury. Accumulation of [beta]APP increased with increasing strain. All stretched BP terminal nerves (<10%, 10-20%, and >20%) significantly differed from the control samples that only underwent the surgical procedure. This study is the first to report in vivo tensile biomechanical properties and structural changes at varying degrees of stretch of the neonatal BP using a clinically relevant neonatal large animal model. Data obtained from the current study will enhance the bio-fidelic responses of existing computational models that simulate neonatal BP injuries. This research will further our understanding of neonatal BP injuries and advance preventative strategies by creating a framework for future studies, including injury-site modeling or surgical planning.

Investigating biomechanical properties and structural changes post-stretch in neonatal brachial plexus

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Investigating biomechanical properties and structural changes post-stretch in neonatal brachial plexus

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