Laryngeal transplantation in minipigs: vascular, myologic and functional outcomes

Abstract

There is no effective way of replacing all the functions of the larynx in those requiring laryngectomy. Regenerative medicine offers promise, but cannot presently deliver implants with functioning neuromuscular units. A single well-documented laryngeal transplant in man was a qualified success, but more information is required before clinical trials may be proposed. We studied the early response of the larynx to laryngeal transplantation between 17 pairs of NIH minipigs full matched at the MHC2 locus. Following iterative technical improvements, pigs had good swallowing and a patent airway at 1 week. No significant changes in mucosal blood flux were observed compared with pre-operative measurements. Changes in muscle morphology and fibre phenotype were observed in transplant muscles retrieved after 7 days: the levels of fast and slow myosin heavy chain (MyHC) protein were reduced and embryonic MyHC was up regulated consistent with denervation induced atrophy. At 1 week laryngeal transplantation can result in good swallowing, and is not associated with clinical evidence of ischemia-reperfusion injury in MHC-matched pigs.

Effects of Functional Electrical Stimulation on Denervated Laryngeal Muscle in a Large Animal Model

“…The decrease in PCA volume of 30-40% over a 20-week denervation period suggests that slow rather than rapid atrophy occurs after denervation in this model. This is consistent with slow atrophy and absence of necrosis found after denervation in other large animals (14,22,35) rather than rodent models of denervation (36,37). The equine model may represent a good system in which to study the effects of electrical stimulation on laryngeal muscle as the larger size of the equine PCA reduces some of the technical considerations for electrode implantation, and endoscopic and volumetric reconstruction techniques allow longitudinal assessment of structure and function.…”

“…Animal models of RLn injury have been previously used to evaluate the use of FES to stimulate a denervated laryngeal musculature. These models have predominantly focused on the dog (8-10), sheep (11,12), cat (13), pig (14)(15)(16), and more recently, horse (17,18). Confounding features of these animal studies have been variation in the parameters used for stimulation, including number of pulses, daily activation rate and rest periods between stimulation, in addition to varying rates of denervation across species and both positive and negative effects of stimulation on muscle integrity and the process of reinnervation have been reported (19)(20)(21)(22).…”

Laryngeal transplantation in minipigs: early immunological outcomes

“…For anatomical reasons, it can be difficult to collect tracheal samples from live pigs without compromising intubation and causing unnecessary stress to the animal [20]. Therefore, only two samples of trachea were collected at induction (T 0 ) and no attempt was made to collect tracheal samples at 48 h. Unsuccessful transplants were due either to problems with the airway (three cases) or failure of the graft to reperfuse; incremental improvements in the surgical technique resolved these problems [12].…”

“…Sixteen fully MHC‐matched, non‐immmunosuppressed transplants were performed using published techniques [5,6,12]. Transplants were female into female or female into male.…”

“…Transplants were female into female or female into male. Full details of the surgical technique, functional outcomes and peri‐operative care are reported in separate papers [12,13].…”