A Novel Rodent Orthotopic Forelimb Transplantation Model That Allows for Reliable Assessment of Functional Recovery Resulting From Nerve Regeneration

Abstract

Improved nerve regeneration and functional outcomes would greatly enhance the utility of vascularized composite allotransplantation (VCA) such as hand and upper extremity transplantation. However, research aimed at achieving this goal has been limited by the lack of a functional VCA animal model. We have developed a novel rat midhumeral forelimb transplant model that allows for the characterization of upper extremity functional recovery following transplantation. At the final end point of 12 weeks, we found that animals with forelimb transplantation including median, ulnar and radial nerve coaptation demonstrated significantly improved grip strength and forelimb function as compared to forelimb transplantation without nerve approximation (grip strength: 1.71N ± 0.57 vs. no appreciable recovery; IBB scale: 2.6 ± 0.7? vs. 0.8 ± 0.40; p = 0.0005), and similar recovery to nerve transection-and-repair only (grip strength: 1.71N ± 0.57 vs. 2.03 ± 0.42.6; IBB scale: 2.6 ± 0.7 vs. 2.8 ± 0.8; p = ns). Moreover, all forelimb transplant animals with nerve coaptation displayed robust axonal regeneration with myelination and reduced flexor muscle atrophy when compared to forelimb transplant animals without nerve coaptation. In conclusion, this is the first VCA small-animal model that allows for reliable and reproducible measurement of behavioral functional recovery in addition to histologic evaluation of nerve regeneration and graft reinnervation.

Evolution of the rat hind limb transplant as an experimental model of vascularized composite allotransplantation: Approaches and advantages

“…However, as the field continues to grow, models focusing on forelimb function in the rat are being developed. 67,68 Kern et al developed a rat allogeneic (BN to Lewis) midhumeral forelimb transplant model that includes cooptation of the median, ulnar and radial nerves. 67 Importantly, this model allowed the investigators to study recovery of not only grip strength but also of behavioral function.…”

“…67,68 Kern et al developed a rat allogeneic (BN to Lewis) midhumeral forelimb transplant model that includes cooptation of the median, ulnar and radial nerves. 67 Importantly, this model allowed the investigators to study recovery of not only grip strength but also of behavioral function. Taking advantage of the propensity of rats to eat a piece of Fruit Loops™ cereal while rolling the treat in a circle using movement of elbow, forearm, wrist and paw, they have developed the first VCA rodent model that can assess behavioral functional recovery in conjunction with histologic evaluation of nerve regeneration and reinnervation.…”

“…The investigators demonstrated that coaptation of all three forearm nerve (median, ulnar and radial) animals had superior grip strength and forearm function in the Fruit Loop test, compared to animals without nerve approximation. 67 More recently, Hanwright et al developed a model of stimulated grip strength by combining aspects of isometric tetanic force testing (ITFT) and volitional grip strength testing (vGST). 68 While ITFT is very accurate, serial measurements are precluded, and vGST is associated with significant variability.…”

Development of a rat forelimb vascularized composite allograft (VCA) perfusion protocol

“…Specifically, rat forelimbs are supplied by smaller arteries and have more complex functions compared to hindlimbs. Thus, the standard hindlimb VCA model does not capture the fine motor function and nerve regeneration capability that would be required for successful upper extremity transplantation [ 19 ]. Here we show to our knowledge, the first rat forelimb VCA procurement and sub-normothermic machine perfusion (SNMP) technique, which we find to be technically distinct from its hindlimb counterpart.…”

Topical Application of Human Wharton’s Jelly Mesenchymal Stem Cells Accelerates Mouse Sciatic Nerve Recovery and is Associated with Upregulated Neurotrophic Factor Expression

“…Peripheral nerve injuries commonly occur as part of trauma or iatrogenically during excision or removal of an adjacent lesion. With the recent interest in vascularized composite allotransplantation, that is, transplantation of a whole limb, the face, or the abdominal wall [7][8][9] to restore function and appearance, the recovery of repairing peripheral nerves becomes crucial for restoration of good graft function [10][11][12][13][14] . Of the various types of nerve injury, complete transection has the worst outcome for regeneration.…”