Endothelial progenitor cell (EPC) therapy has been successfully used in orthopaedic preclinical models to heal bone defects. However, no previous studies have investigated the dose-response relationship between EPC therapy and bone healing. This study aimed to assess the effect of different EPC doses on bone healing in a rat model to define an optimal dose. Five-millimeter segmental defects were created in the right femora of Fischer 344 rats, followed by stabilization with a miniplate and screws. Rats were assigned to one of six groups (control, 0.1 M, 0.5 M, 1.0 M, 2.0 M, and 4.0 M; n = 6), receiving 0, 1 × 105, 5 × 105, 1 × 106, 2 × 106, and 4 × 106 EPCs, respectively, delivered into the defect on a gelatin scaffold. Radiographs were taken every two weeks until the animals were euthanized 10 weeks after surgery. The operated femora were then evaluated using micro-computed tomography and biomechanical testing. Overall, the groups that received higher doses of EPCs (0.5 M, 1.0 M, 2.0 M, and 4.0 M) reached better outcomes. At 10 weeks, full radiographic union was observed in 67% of animals in the 0.5 M group, 83% of animals in the 1.0 M group, and 100% of the animals in the 2.0 M and 4.0 M groups, but none in the control and 0.1 M groups. The 2.0 M group also displayed the strongest biomechanical properties, which significantly improved relative to the control and 0.1 M groups. In summary, this study defined a dose-response relationship between EPC therapy and bone healing, with 2 × 106 EPCs being the optimal dose in this model. Our findings emphasize the importance of dosing considerations in the application of cell therapies aimed at tissue regeneration and will help guide future investigations and clinical translation of EPC therapy.

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The triceps surae (TS) length–tension relationship can be altered by changing the knee joint position, ankle joint position or both. However, studies exploring the effect of muscle length on neuromuscular properties have focused only on knee joint position changes affecting two of the three muscle components of the TS. Thus, the purpose of this study is to compare the neuromuscular properties of the three TS muscles during plantar flexion contractions at two ankle joint positions, 20° dorsiflexed (DF) and 20° plantar flexed (PF). Maximal isometric voluntary strength (MVC), voluntary activation, and evoked contractile properties of the ankle plantar flexors were compared between both ankle joint positions. Additionally, soleus, medial (MG), and lateral (LG) gastrocnemii motor unit discharge rates (MUDRs) were sampled during plantar flexion contractions at 25%, 50%, 75%, and 100% MVC using indwelling tungsten electrodes. MVC and peak twitch torque were lower by ~61% and 70%, respectively, whereas the maximal rate of torque relaxation was 39% faster in the PF compared with the DF position. Voluntary activation (~95%) was unaffected by changes in ankle joint position. LG MUDRs showed no differences between ankle joint positions, regardless of contraction intensity. Submaximal MG and soleus MUDRs showed no differences between the two ankle joint positions, however both muscles had 9% and 20% higher MUDRs in the DF position, respectively. These results provide further evidence for the differential activation among the three components of the TS with the greatest increases in soleus MUDRs compared with the gastrocnemii when the muscles are lengthened.

Low-intensity contractions with blood flow occlusion (BFO) result in neuromuscular adaptations comparable to high-intensity (>70% maximal voluntary contraction, MVC) exercise. Because, BFO exercise can only be applied to limb muscles, it is of interest to explore whether muscles proximal to the occlusion site are affected. Therefore, the purpose was to assess neural activation of the tibialis anterior (TA) when flow is occluded proximal and distal to the active muscle. Five males completed three protocols to observe the effect of BFO on motor unit firing rates (MUFR) of the TA at a fatiguing contraction intensity of ~15% MVC. Two occlusion protocols, one proximal (BFOprox) to, one distal (BFOdis) to the TA were compared to a control (free-flow) protocol time-matched to BFOdis. MVC was significantly reduced following the BFOprox (~41%; P < 0.001) and BFOdis (~27%, p < 0.001), but not following the control protocol (~15%; P = 0.13). Surface EMG during BFOdis and BFOprox increased ~14% and ~28%, respectively, but was not different among protocols. MUFRs for BFOdis and BFOprox were significantly reduced by (~33 and ~23%, respectively; P < 0.01) at task failure. Results indicate that although BFOprox results in the largest reductions of MUFRs, BFOdis shows greater impairments compared to the free-flow control condition. Novelty Bullets •Effects on motor unit firing rates of proximal versus distal blood flow occlusion compared during low-intensity fatiguing task. •Proximal occlusion results in greatest fatigue and reduction in motor unit rates, but distal occlusion elicits more fatigue and rate reduction than a control task.