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Background: Maximal oxygen uptake (VO 2max ) is an important determinant of endurance performance. Heat acclimation/acclimatization (HA/HAz) elicits improvements in endurance performance. Upon heat exposure reduction, intermittent heat training (IHT) may alleviate HA/HAz adaptation decay; however, corresponding VO 2max responses are unknown., Hypothesis: VO 2max is maintained after HAz/HA; IHT mitigates decrements in aerobic power after HAz/HA., Study Design: Interventional study., Level of Evidence: Level 3., Methods: A total of 27 male endurance runners (mean ± SD; age, 36 ± 12 years; body mass, 73.03 ± 8.97 kg; height, 178.81 ± 6.39 cm) completed VO 2max testing at 5 timepoints; baseline, post-HAz, post-HA, and weeks 4 and 8 of IHT (IHT 4 , IHT 8 ). After baseline testing, participants completed HAz, preceded by 5 days of HA involving exercise to induce hyperthermia for 60 minutes in the heat (ambient temperature, 39.13 ± 1.37°C; relative humidity, 51.08 ± 8.42%). Participants were assigned randomly to 1 of 3 IHT groups: once-weekly, twice-weekly, or no IHT. Differences in VO 2max , velocity at VO 2max (vVO 2 ), and maximal heart rate (HR max ) at all 5 timepoints were analyzed using repeated-measure analyses of variance with Bonferroni corrections post hoc., Results: No significant VO 2max or vVO 2 differences were observed between baseline, post-HAz, or post-HA ( P = 0.36 and P = 0.09, respectively). No significant group or time effects were identified for VO 2max or vVO 2 at post-HA, IHT 4 , and IHT 8 ( P = 0.67 and P = 0.21, respectively). Significant HR max differences were observed between baseline and post-HA tests ( P < 0.01). No significant group or time HR max differences shown for post-HA, IHT 4 , and IHT 8 ( P = 0.59)., Conclusion: VO 2max was not reduced among endurance runners after HA/HAz and IHT potentially due to participants' similar aerobic training status and high aerobic fitness levels., Clinical Relevance: HAz/HA and IHT maintain aerobic power in endurance runners, with HAz/HA procuring reductions in HR max ., Competing Interests: The authors report no potential conflicts of interest in the development or publication of this article.

Introduction: Personal protective equipment (PPE) inhibits heat dissipation and elevates heat strain. Impaired cooling with PPE warrants investigation into practical strategies to improve work capacity and mitigate exertional heat illness., Purpose: Examine physiological and subjective effects of forearm immersion (FC), fan mist (MC), and passive cooling (PC) following three intermittent treadmill bouts while wearing PPE., Methods: Twelve males (27 ± 6 years; 57.6 ± 6.2 ml/kg/min; 78.3 ± 8.1 kg; 183.1 ± 7.2 cm) performed three 50-min (10 min of 40%, 70%, 40%, 60%, 50% vVO 2 max) treadmill bouts in the heat (36 °C, 30% relative humidity). Thirty minutes of cooling followed each bout, using one of the three strategies per trial. Rectal temperature (T core ), skin temperature (T sk ), heart rate (HR), heart rate recovery (HRR), rating of perceived exertion (RPE), thirst, thermal sensation (TS), and fatigue were obtained. Repeated-measures analysis of variance (condition x time) detected differences between interventions., Results: Final T core  was similar between trials (P > .05). Cooling rates were larger in FC and MC vs PC following bout one (P < .05). HRR was greatest in FC following bouts two (P = .013) and three (P < .001). T sk , fluid consumption, and sweat rate were similar between all trials (P > .05). TS and fatigue during bout three were lower in MC, despite similar T core  and HR., Conclusion: Utilizing FC and MC during intermittent work in the heat with PPE yields some thermoregulatory and cardiovascular benefit, but military health and safety personnel should explore new and novel strategies to mitigate risk and maximize performance under hot conditions while wearing PPE., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Athletes training in heat experience physiological and perceptual symptoms that risk their safety and performance without adaptation., Purpose: We examined the changes in environmental symptoms, assessed with the Environmental Symptoms Questionnaire (ESQ), during heat acclimatization (HAz), heat acclimation (HA), and intermittent heat training (HT)., Methods: Twenty-seven participants (mean ± standard deviation [M ± SD], age of 35 ± 12 y, VO 2max of 57.7 ± 6.8 mL·kg -1 ·min -1 ) completed five trials involving 60 mins of running (60% vVO 2max ) followed by a 4 km time trial in heat (M ± SD, temperature of 35.5 ± 0.7 °C, humidity of 46.4 ± 1.5%). The trials occurred at baseline, post-HAz, post-HA, at week 4 of HT (post-HT4), and at week 8 of HT (post-HT8). The participants completed HT once/week (HT MIN ), completed HT twice/week (HT MAX ), or did not complete HT (HT CON ). ESQ symptoms, thermal sensation (TS), and heart rate (HR) were measured pre- and post-trial., Results: Post-ESQ symptoms improved post-HA (3[0.40, 4.72], p = 0.02) and post-HAz (3[0.35, 5.05], p = 0.03) from baseline. During HT, symptoms improved in the HT MAX group and worsened in the HT MIN and HT CON groups. Symptoms improved in the HT MAX group versus the HT CON group at post-HT8 (4[1.02, 7.23], p = 0.012). Higher TS and HR values were weakly associated with ESQ symptoms during HT ( r = 0.20, p = 0.04), only explaining 20% of variance., Conclusions: ESQ symptoms improved during HAz, HA, and HT 2x/week. ESQ symptoms were not statistically correlated with HR during exercise heat stress. TS was not sensitive to detecting adaptation and did not subjectively change. The ESQ may be valuable in monitoring adaptation and may contribute to performance post-acclimation.

Recruiting companies recommend elite female soccer players be ≥165 cm (5'5″) in stature. This study investigated if stature limits match-playing time and performance in elite World Cup soccer among players, positions, and countries. We hypothesized stature would not affect match-playing time or performance. Descriptive data were collected on 552 players from 2019 FIFA Women's World Cup. Odds ratios determined likelihood of starting for players <165 cm and ≥165 cm. ANOVAs compared playing time between stature groups, among positions, and between countries. Performance factors including assists, goals, attempts, corners, shots blocked, and defending blocks were reported. Independent t-tests compared differences between players (≥165 cm, < 165 cm). Data are reported, mean difference [95% confidence interval] [MD (95%CI)] and effect sizes (ES). On average, 32.3% of players were <165 cm. Of total players, no differences existed in total minutes ( F =  0.98, p  = 0.32) , matches ( F  = 0.27 p  = 0.59), or average minutes per match ( F =  0.48, p  = 0.49) between stature groups, regardless of position. No differences existed in playing time between players <165 cm and ≥165 cm among any positions ( p  > 0.05), or between countries ( p  > 0.05). Taller mid-fielders exhibited greater performance in goals, assists, attempts, shots blocked, and defending blocks (MD [95%CI] ES; assists, -0.44[-0.76,-0.11]0.59, p  = 0.009; goals, -0.35[-0.69,-0.01]0.44, p  = 0.047); attempts, 3.14[1.38, 4.90]0.80, p  = 0.001; corners, 2.04[0.12, 3.95]0.48, p  = 0.037; shots blocked, 0.96[0.40, 1.51]0.75, p  = 0.001; defending blocks, 0.43[0.32,0.82]0.48, p  = 0.035), however, actual differences were minimal. Our findings indicate stature does not inhibit playing and performing elite women's soccer, as nearly one-third of players were <165 cm., Competing Interests: Author GC was employed by the United States Soccer Federation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Manning, Sekiguchi, Benjamin, Spaulding, Dierickx, Spaulding, Davenport, Picard-Busky, Chiampas, Nassis and Casa.)

Assessing the adaptation of rectal temperature (T rec ) is critical following heat acclimatization (HAz) and heat acclimation (HA) because it is associated with exercise performance and safety; however, more feasible and valid methods need to be identified. The purpose of this study was to predict adaptations in T rec from heart rate (HR), sweat rate (SR), and thermal sensation (TS) using predictive modeling techniques. Twenty-five male endurance athletes (age, 36 ± 12 y; VO 2max , 57.5 ± 7.0 mL⋅kg -1 ⋅min -1 ) completed three trials consisting of 60 min running at 59.3 ± 1.7% vVO 2max in a hot environment. During trials, the highest HR and TS, SR, and T rec at the end of trials were recorded. Following a baseline trial, participants performed HAz followed by a post-HAz trial and then completed five days HA, followed by a post-HA trial. A decision tree indicated cut-points of HR (<-13 bpm), SR (>0.3 L·h -1 ), and TS (≤-0.5) to predict lower T rec . When two or three variables met cut-points, the probability of accuracy of showing lower T rec was 95.7%. Greater adaptations in T rec were observed when two or three variables met cut-points (-0.71 ± 0.50 °C) compared to one (-0.13 ± 0.36 °C, p < 0.001) or zero (0.0 3 ± 0.38 °C, p < 0.001). Specificity was 0.96 when two or three variables met cut-points to predict lower T rec . These results suggest using heart rate, sweat rate, and thermal sensation adaptations to indicate that the adaptations in T rec is beneficial following heat adaptations, especially in field settings, as a practical and noninvasive method.

Background: The purpose of this study was to investigate effects of heat acclimatization (HAz) followed by heat acclimation (HA), and intermittent heat training (IHT) on time-trial performance., Hypothesis: Time-trial performance will improve after HA and will further improve with twice a week of IHT., Study Design: Interventional study., Level of Evidence: Level 3., Methods: A total of 26 male athletes (mean ± SD; age, 35 ± 12 years; body mass, 72.8 ± 8.9 kg; peak oxygen consumption [VO 2peak ], 57.3 ± 6.7 mL·kg -1 ·min -1 ) completed five 4-km time trials (baseline, post-HAz, post-HA, post-IHT4, post-IHT8) in the heat (ambient temperature, 35.4°C ± 0.3°C; relative humidity, 46.7% ± 1.2%) on a motorized treadmill. After baseline time trial, participants performed HAz (109 ± 10 days) followed by post-HAz time trial. Then, participants completed 5 days of HA, which involved exercising to induce hyperthermia (38.50°C-39.75°C) for 60 minutes. Participants were then divided into 3 groups and completed IHT either twice per week (IHT MAX ), once per week (IHT MIN ), or not at all (IHT CON ) over an 8-week period. The exercise used for the IHT matched the HA. Four-kilometer time trials were performed after 4 weeks (post-IHT4) and 8 weeks of IHT (post-IHT8)., Results: Time trial was faster in post-HA (17.98 ± 2.51 minutes) compared with baseline (18.61 ± 3.06 minutes; P = 0.037) and post-HAz (18.66 ± 3.12 minutes; P = 0.023). Percentage change in time trial was faster in IHT MAX (-3.9% ± 5.2%) compared with IHT CON (11.5% ± 16.9%) ( P = 0.020) and approached statistical significance with large effect (effect size = 0.96) compared with IHT MIN (1.6% ± 6.2%; P = 0.059) at post-IHT8. Additionally, IHT MAX (-2.2% ± 4.2%) was faster than IHT CON (3.6% ± 6.9%) ( P = 0.05) at post-IHT4., Conclusion: These results indicate that HA after HAz induces additional improvement in time-trial performance. IHT twice per week shows improvement after 8 weeks, while once per week maintains performance for 8 weeks. No IHT results in a loss of adaptations after 4 weeks and even greater losses after 8 weeks., Clinical Relevance: HA after HAz improves time-trial performance, twice a week of IHT improves performance further, and once a week of IHT maintains performance for at least 8 weeks.

The purpose of this study was to examine the changes in metabolic heat production (Hprod), evaporative heat loss (Hevap), and dry heat loss (Hdry), following heat acclimatization (HAz) and heat acclimation (HA). Twenty-two male endurance athletes (mean ± standard deviation; age, 37 ± 12 y; body mass, 73.4 ± 8.7 kg; height, 178.7 ± 6.8 cm; and VO2max, 57.1 ± 7.2 mL·kg−1·min−1) completed three trials (baseline; post-HAz; and post-HA), which consisted of 60 min steady state exercise at 59 ± 2% velocityVO2max in the heat (ambient temperature [Tamb], 35.2 ± 0.6 °C; relative humidity [%rh] 47.5 ± 0.4%). During the trial, VO2 and RER were collected to calculate Hprod, Hevap, and Hdry. Following the baseline trial, participants completed self-directed outdoor summer training followed by a post-HAz trial. Then, five days of HA were completed over eight days in the heat (Tamb, 38.7 ± 1.1 °C; %rh, 51.2 ± 2.3%). During the HA sessions, participants exercised to maintain hyperthermia (38.50 °C and 39.75 °C) for 60 min. Then, a post-HA trial was performed. There were no differences in Hprod between the baseline (459 ± 59 W·m−2), post-HAz (460 ± 61 W·m−2), and post-HA (464 ± 55 W·m−2, p = 0.866). However, Hevap was significantly increased post-HA (385 ± 84 W·m−2) compared to post-HAz (342 ± 86 W·m−2, p = 0.043) and the baseline (332 ± 77 W·m−2, p = 0.037). Additionally, Hdry was significantly lower at post-HAz (125 ± 8 W·m−2, p = 0.013) and post-HA (121 ± 10 W·m−2, p < 0.001) compared to the baseline (128 ± 7 W·m−2). Hdry at post-HA was also lower than post-HAz (p = 0.049). Hprod did not change following HAz and HA. While Hdry was decreased following HA, the decrease in Hdry was smaller than the increases in Hevap. Adaptations in body heat exchange can occur by HA following HAz.

Objectives: To examine the efficacy of weekly and bi-weekly heat training to maintain heat acclimatization (HAz) and heat acclimation (HA) for 8 weeks in aerobically trained athletes., Design: Randomized, between-group., Methods: Twenty-four males (mean [m ± standard deviation [sd]; (age, 34 ± 12 y; body mass, 72.6 ± 8.8 kg, VO 2peak , 57.7 ± 6.8 mL·kg -1 ·min -1 ) completed five trials (baseline, following HAz, following HA (HAz + HA), four weeks into heat training [HT WK4 ], and eight weeks into HT [HT WK8 ] that involved 60 min of steady-state exercise (59.1 ± 1.8% vVO 2peak ) in an environmental laboratory (wet bulb globe temperature [WBGT], 29.6 ± 1.4 °C) on a motorized treadmill. Throughout exercise, heart rate (HR) and rectal temperature (T rec ) were recorded. Following HAz + HA, participants were assigned to three groups: control group (HT 0 ), once per week heat training (HT 1 ), and twice per week heat training (HT 2 ). HT involved heated exercise (WBGT, 33.3 ± 1.3 °C) to achieve hyperthermia (38.5-39.75 °C) for 60 min. Repeated measures ANOVAs were used to determine differences., Results: HAz + HA resulted in significant improvements in HR (p < 0.001) and T rec (p < 0.001). At HT WK8 , HR was significantly higher in HT 0 (174 ± 22 beats⋅min -1 ) compared to HT 2 (151 ± 17 beats⋅min -1 , p < 0.023), but was not different than HT 1 (159 ± 17 beats⋅min -1 , p = 0.112). There was no difference in % change of T rec from post-HAz + HA to HT WK4 (0.6 ± 1.3%; p = 0.218), however, HT WK8 (1.8 ± 1.4%) was significantly greater than post-HAz + HA in HT 0 (p = 0.009)., Conclusions: Bi-weekly HT provided clear evidence for the ability to maintain physiological adaptions for 8 weeks following HA., (Copyright © 2021 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

The purpose of this study was to examine the effect of heat acclimation (HA) on thirst levels, sweat rate, and percentage of body mass loss (%BML), and changes in fluid intake factors throughout HA induction. Twenty-eight male endurance athletes (mean ± SD; age, 35 ± 12 years; body mass, 73.0 ± 8.9 kg; maximal oxygen consumption, 57.4 ± 6.8 ml·kg-1·min-1) completed 60 min of exercise in a euhydrated state at 58.9 ± 2.3% velocity of maximal oxygen consumption in the heat (ambient temperature, 35.0 ± 1.3 °C; relative humidity, 48.0 ± 1.3%) prior to and following HA where thirst levels, sweat rate, and %BML were measured. Then, participants performed 5 days of HA while held at hyperthermia (38.50-39.75 °C) for 60 min with fluid provided ad libitum. Sweat volume, %BML, thirst levels, and fluid intake were measured for each session. Thirst levels were significantly lower following HA (pre, 4 ± 1; post, 3 ± 1, p < .001). Sweat rate (pre, 1.76 ± 0.42 L/hr; post, 2.00 ± 0.60 L/hr, p = .039) and %BML (pre, 2.66 ± 0.53%; post, 2.98 ± 0.83%, p = .049) were significantly greater following HA. During HA, thirst levels decreased (Day 1, 4 ± 1; Day 2, 3 ± 2; Day 3, 3 ± 2; Day 4, 3 ± 1; Day 5, 3 ± 1; p < .001). However, sweat volume (Day 1, 2.34 ± 0.67 L; Day 2, 2.49 ± 0.58 L; Day 3, 2.67 ± 0.63 L; Day 4, 2.74 ± 0.61 L; Day 5, 2.74 ± 0.91 L; p = .010) and fluid intake (Day 1, 1.20 ± 0.45 L; Day 2, 1.52 ± 0.58 L; Day 3, 1.69 ± 0.63 L; Day 4, 1.65 ± 0.58 L; Day 5, 1.74 ± 0.51 L; p < .001) increased. In conclusion, thirst levels were lower following HA even though sweat rate and %BML were higher. Thirst levels decreased while sweat volume and fluid intake increased during HA induction. Thus, HA should be one of the factors to consider when planning hydration strategies.

Euhydration remains a challenge in children due to lack of access and unpalatability of water and to other reasons. The purpose of this study was to determine if the availability/access to a beverage (Creative Roots ® ) influences hydration in children and, therefore, sleep quality and mood. Using a crossover investigation, 46 participants were randomly assigned to a control group (CON) or an intervention group and received Creative Roots ® (INT) for two-week periods. We recorded daily first morning and afternoon urine color (Ucol), thirst perception, and bodyweight of the two groups. Participants reported to the lab once per week and provided first morning urine samples to assess Ucol, urine specific gravity (USG), and urine osmolality (Uosmo). Participants also completed the questionnaires Profile of Mood States-Adolescents (POMS-a) and Pittsburgh Sleep Quality Index (PSQI). Dependent t -tests were used to assess the effects of the intervention on hydration, mood, and sleep quality. Uosmo was greater and Ucol was darker in the control group (mean ± SD) [Uosmo: INT = 828 ± 177 mOsm·kg -1 , CON = 879 ± 184 mOsm·kg -1 , ( p = 0.037], [Ucol:INT = 5 ± 1, CON = 5 ± 1, p = 0.024]. USG, POMS-a, and PSQI were not significant between the groups. At-home daily afternoon Ucol was darker in the control group [INT = 3 ± 1, CON = 3 ± 1, p = 0.022]. Access to Creative Roots ® provides a small, potentially meaningful hydration benefit in children. However, children still demonstrated consistent mild dehydration based on Uosmo, despite consuming the beverage.

The purpose of this study was to assess the effectiveness of heat acclimatization (HAz) followed by heat acclimation (HA) on physiological adaptations. 25 male endurance athletes (age 36 ± 12 y, height 178.8 ± 6.39 cm, body mass 73.03 ± 8.97 kg, and VO 2peak 57.5 ± 7.0 mL·kg -1 ·min -1 ) completed HAz and HA. HAz was 3 months of self-directed summer training. In the laboratory, a 5-day HA prescribed exercise to target a hyperthermic zone (HZHA) of T rec between 38.50 and 39.75 °C for 60 min. Exercise trials were 60 min of running (59% ± 2% VO 2peak ) in an environmental chamber (wet bulb globe temperature 29.53 ± 0.63 °C) and administered at: baseline, post-HAz, and post-HAz+HA. Measured variables included internal body temperature (T rec ), heart rate (HR), and sweat rate (SR). Repeated measure ANOVAs and post hoc comparisons were used to assess statistically significant ( p < 0.05) differences. T rec was lower post-HAz+HA (38.03 ± 0.39 °C) than post-HAz (38.25 ± 0.42 °C, p = 0.009) and baseline (38.29 ± 0.37 °C, p = 0.005). There were no differences between baseline and post-HAz ( p = 0.479) in T rec . HR was lower post-HAz (143 ± 12 bpm, p = 0.002) and post-HAz+HA (134 ± 11 bpm, p < 0.001) than baseline (138 ± 14 bpm). HR was lower post-HAz+HA than post-HAz ( p = 0.013). SR was higher post-HAz+HA (1.93 ± 0.47 L·h -1 ) than post-HAz (1.76 ± 0.43 L·h -1 , p = 0.027). Combination HAz and HA increased physiological outcomes above HAz. This method can be used to improve performance and safety in addition to HAz alone.

Introduction: Macrophage-driven inflammation is a key feature of the early period following tendon repair, but excessive inflammation has been associated with poor clinical outcomes. Modulation of the inflammatory environment using molecular or cellular treatments may provide a means to enhance tendon healing., Methods: To examine the effect of pro-inflammatory cytokines secreted by macrophages on tendon fibroblasts (TF), we established in vitro models of cytokine and macrophage-induced inflammation. Gene expression, protein expression, and cell viability assays were used to examine TF responses. In an effort to reduce the negative effects of inflammatory cytokines on TFs, adipose-derived mesenchymal stromal cells (ASCs) were incorporated into the model and their ability to modulate inflammation was investigated., Results: The inflammatory cytokine interleukin 1 beta (IL-1β) and macrophages of varying phenotypes induced up-regulation of pro-inflammatory factors and matrix degradation factors and down-regulation of factors related to extracellular matrix formation by TFs in culture. ASCs did not suppress these presumably negative effects induced by IL-1β. However, ASC co-culture with M1 (pro-inflammatory) macrophages successfully suppressed the effects of M1 macrophages on TFs by inducing a phenotypic switch from a pro-inflammatory macrophage phenotype to an anti-inflammatory macrophage phenotype, thus resulting in exposure of TFs to lower levels of pro-inflammatory cytokines (e.g., IL-1β, tumor necrosis factor alpha (TNFα))., Conclusions: These findings suggest that IL-1β and M1 macrophages are detrimental to tendon healing and that ASC-mediated modulation of the post-operative inflammatory response may be beneficial for tendon healing.

Despite advances in surgical techniques over the past three decades, tendon repairs remain prone to poor clinical outcomes. Previous attempts to improve tendon healing have focused on the later stages of healing (i.e., proliferation and matrix synthesis). The early inflammatory phase of tendon healing, however, is not fully understood and its modulation during healing has not yet been studied. Therefore, the purpose of this work was to characterize the early inflammatory phase of flexor tendon healing with the goal of identifying inflammation-related targets for future treatments. Canine flexor tendons were transected and repaired using techniques identical to those used clinically. The inflammatory response was monitored for 9 days. Temporal changes in immune cell populations and gene expression of inflammation-, matrix degradation-, and extracellular matrix-related factors were examined. Gene expression patterns paralleled changes in repair-site cell populations. Of the observed changes, the most dramatic effect was a greater than 4,000-fold up-regulation in the expression of the pro-inflammatory factor IL-1β. While an inflammatory response is likely necessary for healing to occur, high levels of pro-inflammatory cytokines may result in collateral tissue damage and impaired tendon healing. These findings suggest that future tendon treatment approaches consider modulation of the inflammatory phase of healing., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Reattachment of tendon to bone has been a challenge in orthopedic surgery. The disparate mechanical properties of the two tissues make it difficult to achieve direct surgical repair of the tendon-to-bone insertion. Healing after surgical repair typically does not regenerate the natural attachment, a complex tissue that connects tendon and bone across a gradient in both mineral content and cell phenotypes. To facilitate the regeneration of the attachment, our groups have developed a nanofiber-based scaffold with a graded mineral coating to mimic the mineral composition of the native tendon-to-bone insertion. In the present work, we evaluated the ability of this scaffold to induce graded osteogenesis of adipose-derived mesenchymal stem cells (ASCs). Results from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferating cell nuclear antigen staining indicated that cell proliferation was negatively correlated with the mineral content. In contrast, alkaline phosphatase staining, an indicator of osteogenesis, was positively correlated with the mineral content. Likewise, runt-related transcription factor 2 (an early marker of osteoblast differentiation) and osteocalcin (a late marker of osteoblast differentiation) immunostaining were both positively correlated with the mineral content. These results indicate that a gradient in mineral content on the surface of a nanofiber scaffold is capable of inducing graded differentiation of ASCs into osteoblasts for enthesis repair.

Outcomes after tendon repair are often unsatisfactory, despite improvements in surgical techniques and rehabilitation methods. Recent studies aimed at enhancing repair have targeted the paucicellular nature of tendon for enhancing repair; however, most approaches for delivering growth factors and cells have not been designed for dense connective tissues such as tendon. Therefore, we developed a scaffold capable of delivering growth factors and cells in a surgically manageable form for tendon repair. Platelet-derived growth factor BB (PDGF-BB), along with adipose-derived mesenchymal stem cells (ASCs), were incorporated into a heparin/fibrin-based delivery system (HBDS). This hydrogel was then layered with an electrospun nanofiber poly(lactic-co-glycolic acid) (PLGA) backbone. The HBDS allowed for the concurrent delivery of PDGF-BB and ASCs in a controlled manner, while the PLGA backbone provided structural integrity for surgical handling and tendon implantation. In vitro studies verified that the cells remained viable, and that sustained growth factor release was achieved. In vivo studies in a large animal tendon model verified that the approach was clinically relevant, and that the cells remained viable in the tendon repair environment. Only a mild immunoresponse was seen at dissection, histologically, and at the mRNA level; fluorescently labeled ASCs and the scaffold were found at the repair site 9days post-operatively; and increased total DNA was observed in ASC-treated tendons. The novel layered scaffold has the potential for improving tendon healing due to its ability to deliver both cells and growth factors simultaneously in a surgically convenient manner., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Tendon-to-bone healing is typically poor, with a high rate of repair-site rupture. Bone loss after tendon-to-bone repair may contribute to poor outcomes. Therefore, we hypothesized that the local application of the osteogenic growth factor bone morphogenetic protein 2 (BMP-2) would promote bone formation, leading to improved repair-site mechanical properties. Intrasynovial canine flexor tendons were injured in Zone 1 and repaired into bone tunnels in the distal phalanx. BMP-2 was delivered to the repair site using either a calcium phosphate matrix (CPM) or a collagen sponge (COL) carrier. Each animal also received carrier alone in an adjacent repair to serve as an internal control. Repairs were evaluated at 21 days using biomechanical, radiographic, and histologic assays. Although an increase in osteoid formation was noted histologically, no significant increases in bone mineral density occurred. When excluding functional failures (i.e., ruptured and gapped repairs), mechanical properties were not different when comparing BMP-2/CPM groups with carrier controls. A significantly higher percentage of BMP-2 treated specimens had a maximum force <20 N compared to carrier controls. While tendon-to-bone healing can be enhanced by addressing the bone loss that typically occurs after surgical repair, the delivery of BMP-2 using the concentrations and methods of the current study did not improve mechanical properties over carrier alone. The anticipated anabolic effect of BMP-2 was insufficient in the short time frame of this study to counter the post-repair loss of bone., (Copyright © 2012 Orthopaedic Research Society.)

Despite advances in surgical technique, rotator cuff repairs are plagued by a high rate of failure. This failure rate is in part due to poor tendon-to-bone healing; rather than regeneration of a fibrocartilaginous attachment, the repair is filled with disorganized fibrovascular (scar) tissue. Transforming growth factor beta 3 (TGF-β3) has been implicated in fetal development and scarless fetal healing and, thus, exogenous addition of TGF-β3 may enhance tendon-to-bone healing. We hypothesized that: TGF-β3 could be released in a controlled manner using a heparin/fibrin-based delivery system (HBDS); and delivery of TGF-β3 at the healing tendon-to-bone insertion would lead to improvements in biomechanical properties compared to untreated controls. After demonstrating that the release kinetics of TGF-β3 could be controlled using a HBDS in vitro, matrices were incorporated at the repaired supraspinatus tendon-to-bone insertions of rats. Animals were sacrificed at 14-56 days. Repaired insertions were assessed using histology (for inflammation, vascularity, and cell proliferation) and biomechanics (for structural and mechanical properties). TGF-β3 treatment in vivo accelerated the healing process, with increases in inflammation, cellularity, vascularity, and cell proliferation at the early timepoints. Moreover, sustained delivery of TGF-β3 to the healing tendon-to-bone insertion led to significant improvements in structural properties at 28 days and in material properties at 56 days compared to controls. We concluded that TGF-β3 delivered at a sustained rate using a HBDS enhanced tendon-to-bone healing in a rat model., (Copyright © 2011 Orthopaedic Research Society.)

We have demonstrated the fabrication of "aligned-to-random" electrospun nanofiber scaffolds that mimic the structural organization of collagen fibers at the tendon-to-bone insertion site. Tendon fibroblasts cultured on such a scaffold exhibited highly organized and haphazardly oriented morphologies, respectively, on the aligned and random portions.