Stem Cells for Augmenting Tendon Repair

Tendon healing is fraught with complications such as reruptures and adhesion formation due to the formation of scar tissue at the injury site as opposed to the regeneration of native tissue. Stem cells are an attractive option in developing cell-based therapies to improve tendon healing. However, several questions remain to be answered before stem cells can be used clinically. Specifically, the type of stem cell, the amount of cells, and the proper combination of growth factors or mechanical stimuli to induce differentiation all remain to be seen. This paper outlines the current literature on the use of stem cells for tendon augmentation

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Summary Tendons are often subject to age related degenerative changes that coincide with a diminished regenerative capacity. Torn tendons often heal by forming scar tissue that is structurally weaker than healthy native tendon tissue, predisposing to mechanical failure. There is increasing interest in providing biological stimuli to increase the tendon reparative response. Stem cells in particular are an exciting and promising prospect as they have the potential to provide appropriate cellular signals to encourage neotendon formation during repair rather than scar tissue. Currently, a number of issues need to be investigated further before it can be determined whether stem cells are an effective and safe therapeutic option for encouraging tendon repair. This review explores the in-vitro and invivo evidence assessing the effect of stem cells on tendon healing, as well as the potential clinical applications

Mechanical and chemical properties of rotator cuff tendons

Shoulder disease is the third most common musculoskeletal problem, and rotator cuff tendon tears account for the greatest proportion of shoulder complaints. Rotator cuff tears are estimated to affect between 5-30% of adults, with higher incidences of tearing and failure to heal in elderly patients, placing a huge socioeconomic burden on an ageing British population. Serious concern arises as a large proportion of technically correct surgical repairs re-rupture. The intra-articular environment of the tendon often precludes normal healing and surgical repair is often necessary to improve pain and restore some function. It is feasible that there may be an inherent physiological or biomechanical defect in the tissue that prevents complete healing without some further augmentation to the surgical repair. Improved understanding of the biochemical and biomechanical changes in torn rotator cuff tendons may help to reduce the high rerupture rates. This study aimed to characterise normal, and different sized rotator cuff tendon tears from small samples obtained intraoperatively to try to use tests that may potentially be clinically useful in the future. Tendon samples were mechanically tested using dynamic shear analysis, a form of rheology, to overcome gripping and slippage problems of very small specimens. It was found that torn tendons had a significantly reduced storage modulus compared to normal tendons, particularly for massive tears. Chemical analysis of tendons using Fourier transform infrared spectroscopy revealed that partial and different sized rotator cuff tendon tears are chemically distinguishable. The onset of rotator cuff tear pathology is mainly due to an alteration of the collagen structural arrangements, with associated changes in lipids and carbohydrates. Collagen structural changes in small and massive tendons were quantified using differential scanning calorimetry, which allows measurement of collagen thermal properties as a reflection of their structural integrity. Small and massive tendon tears had reduced thermal properties and hence reduced collagen integrity when compared to normal tendons, although there was no difference between the two tear groups. Gene expression differences between the small, massive tears and normal tendons were studied using microarray analysis, and revealed that the different groups were biologically distinguishable. Microarray gene profiles of human rotator cuff tendon tears suggested a key pathogenesis role for various extracellular matrix (ECM) genes, such as aggrecan, matrix metalloproteinases (MMPs) and a disintegrin and metallopeptidases (ADAMs). Rotator cuff tendon tears involve complex gene and biochemical changes, which particularly affect collagen and ECM components. These may interact and result in reduced mechanical properties of torn tendons. A growing interest has been shown in augmenting rotator cuff tendon repairs, for example with repair patches. Mechanical assessment of four commercially available repair patches has demonstrated wide variations between all patches and at least some reduced mechanical properties when compared to human rotator cuff tendons. Surgeons should be aware of the need to address and improve the biology and the mechanical properties of torn rotator cuff tendons when treating and possibly repairing these defects. The differences in different sized rotator cuff tendon tears should also be appreciated, as all tears are not a uniform homogenous group. It is possible that the future may increasingly involve tailoring treatments to specific tear characteristics, although much greater work is required in this area

Mesenchymal stem cell applications to tendon healing

Tendons are often subject to age related degenerative changes that coincide with a diminished regenerative capacity. Torn tendons often heal by forming scar tissue that is structurally weaker than healthy native tendon tissue, predisposing to mechanical failure. There is increasing interest in providing biological stimuli to increase the tendon reparative response. Stem cells in particular are an exciting and promising prospect as they have the potential to provide appropriate cellular signals to encourage neotendon formation during repair rather than scar tissue. Currently, a number of issues need to be investigated further before it can be determined whether stem cells are an effective and safe therapeutic option for encouraging tendon repair. This review explores the in-vitro and invivo evidence assessing the effect of stem cells on tendon healing, as well as the potential clinical application

The Effect of Platelet-Rich Plasma (PRP) on Muscle Contusion Healing in a Rat Model.

Background: Current therapy for muscle contusions is usually limited to nonsteroidal anti-inflammatory drugs and/or use of the RICE principle (rest, ice, compression, elevation); thus, other forms of treatment that can potentially accelerate the rate of healing are desirable. Hypotheses: A local injection of platelet-rich plasma (PRP) would lead to accelerated healing rates compared with controls; also, delayed administration of PRP would lead to a blunted response compared with immediate treatment. Study Design: Controlled laboratory study. Methods: Forty-six male Lewis rats each underwent a single blunt, nonpenetrating impact to the gastrocnemius muscle via a drop-mass technique and subsequently received either a single injection of saline into the area of injury immediately after injury (controls, n = 11) or rat PRP (either immediately after injury [PRP day 0, n = 12], the first day after injury [PRP day 1, n = 12], or the third day after injury [PRP day 3, n = 11]). The primary outcome was maximal isometric torque strength of the injured muscle, which was assessed before injury as well as on postinjury days 1, 4, 7, 10, and 14. All animals were sacrificed on postinjury day 15. Histological and immunohistochemical analyses were performed on 6 specimens from each group after sacrifice. Results: The mean platelet concentration in the PRP was 2.19 × 106 (±2.69 × 105)/μL. The mean white blood cell count in the PRP was 22.54 × 103/μL. Each group demonstrated statistically significant decreases in maximal isometric torque strength after injury when compared with preinjury levels, followed by significant increases back toward baseline values by postinjury day 14 (controls, 90.6% ± 7.90%; PRP day 0, 105.0% ± 7.60%; PRP day 1, 92.4% ± 7.60%; PRP day 3, 77.8% ± 7.90%) (P = .121). There were no statistically significant differences between the treatment and control groups at any of the time points. There were also no statistically significant differences between any of the groups in the percentage of centronucleated fibers (controls, 3.31% ± 5.10%; PRP day 0, 0.62% ± 1.59%; PRP day 1, 3.24% ± 5.77%; PRP day 3, 2.13% ± 3.26%) (P = .211) or the presence of inflammatory cells and macrophages. Conclusion: In this rat contusion model, a local injection of PRP into the injured gastrocnemius muscle resulted in no significant differences in functional or histological outcomes, indicating no likely benefit to healing. Additionally, there was no significant difference between immediate or delayed administration of PRP. Clinical Relevance: Before PRP can be recommended for the treatment of muscle contusion injuries, further translational and clinical investigations need to be performed

Chronic social stress blunts core body temperature and molecular rhythms of Rbm3 and Cirbp in mouse lateral habenula

Chronic social stress in mice causes behavioural and physiological changes that result in perturbed rhythms of body temperature, activity and sleep-wake cycle. To further understand the link between mood disorders and temperature rhythmicity in mice that are resilient or susceptible to stress, we measured core body temperature (Tcore) before and after exposure to chronic social defeat stress (CSDS). We found that Tcore amplitudes of stress-resilient and susceptible mice are dampened during exposure to CSDS. However, following CSDS, resilient mice recovered temperature amplitude faster than susceptible mice. Furthermore, the interdaily stability (IS) of temperature rhythms was fragmented in stress-exposed mice during CSDS, which recovered to control levels following stress. There were minimal changes in locomotor activity after stress exposure which correlates with regular rhythmic expression of Prok2 - an output signal of the suprachiasmatic nucleus. We also determined that expression of thermosensitive genes Rbm3 and Cirbp in the lateral habenula (LHb) were blunted 1 day after CSDS. Rhythmic expression of these genes recovered 10 days later. Overall, we show that CSDS blunts Tcore and thermosensitive gene rhythms. Tcore rhythm recovery is faster in stress-resilient mice, but Rbm3 and Cirbp recovery is uniform across the phenotypes