Platelet rich plasma and mechanical loading in regenerative tendon repair

Abstract Tendon injuries and tendinopathy are a growing problem in the aging but physically active population as well as athletes. Tendons have highly ordered matrix and undergo complex changes during the remodelling phase of tendon healing. Moreover, anaerobic metabolism and poor vascular network contribute to slow adaptation of tissue to the remodelled matrix which consequently results in slow and compromised healing. Such a destitute and slow healing process necessitates development of new and effective therapies and to combine therapies to obtain possibly synergistic effects. Addressing this clinical requirement, the work presented in this thesis investigates the role of two emerging treatment options, platelet rich plasma (pRP) and mechanical loading, on tendon healing. The effects of PRP, a rich autologous source of growth factors, on tendon cells was studied by modelling important stages of tendon healing in vitro. Key parameters such as cellular migration, chemotaxis, viability and senescence were investigated by means of different culturing and staining techniques together with microscopic analyses. PRP significantly increased migration and chemotaxis in human pnmary tenocyte culture. Moreover, PRP protected human tenocytes against challenging environments created by known tendon damaging drugs, dexamethasone and, ciprofloxacin, as well as the injury relevant condition of hypoxia. 11 Concurrently, an in vitro rat tail tendon injury model and static loading device was developed to assess the effect of static mechanical loading and PRP on the biochemical and biomechanical properties of tendon at the tissue level. This in vitro system was also used to investigate the synergistic effects of PRP and mechanical loading on tendon healing. Both PRP and mechanical loading helped to improve the biomechanical and biochemical properties of damaged tendon in vitro. In conclusion, the positive effects of PRP on key cellular parameters such as cell survival, migration and chemotaxis and also mechanical and biochemical properties of tendon tissue make it an important option for faster and less invasive tendon treatment. Additionally, an in vitro tendon injury model together with the mechanical loading device provide a new tool to investigate the mechanical boundary conditions suitable for treating different types of tendon disorders. The findings from the current study points towards the. significant contribution of PRP and mechanical loading to the healing process in tendons and could serve as a promising starting point for developing integrated therapeutic modalities to improve the quality and speed of recovery from tendon injury. 111.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Platelet rich plasma and mechanical loading in regenerative tendon repair

Tendon injuries and tendinopathy are a growing problem in the aging but physically active population as well as athletes. Tendons have highly ordered matrix and undergo complex changes during the remodelling phase of tendon healing. Moreover, anaerobic metabolism and poor vascular network contribute to slow adaptation of tissue to the remodelled matrix which consequently results in slow and compromised healing. Such a destitute and slow healing process necessitates development of new and effective therapies and to combine therapies to obtain possibly synergistic effects.Addressing this clinical requirement, the work presented in this thesis investigates the role of two emerging treatment options, platelet rich plasma (PRP) and mechanical loading, on tendon healing.The effects of PRP, a rich autologous source of growth factors, on tendon cells was studied by modelling important stages of tendon healing in vitro. Key parameters such as cellular migration, chemotaxis, viability and senescence were investigated by means of different culturing and staining techniques together with microscopic analyses.PRP significantly increased migration and chemotaxis in human primary tenocyte culture. Moreover, PRP protected human tenocytes against challenging environments created by known tendon damaging drugs, dexamethasone and ciprofloxacin, as well as the injury relevant condition of hypoxia.Concurrently, an in vitro rat tail tendon injury model and static loading device was developed to assess the effect of static mechanical loading and PRP on the biochemical and biomechanical properties of tendon at the tissue level. This in vitro system was also used to investigate the synergistic effects of PRP and mechanical loading on tendon healing. Both PRP and mechanical loading helped to improve the biomechanical and biochemical properties of damaged tendon in vitro.In conclusion, the positive effects of PRP on key cellular parameters such as cell survival, migration and chemotaxis and also mechanical and biochemical properties of tendon tissue make it an important option for faster and less invasive tendon treatment. Additionally, an in vitro tendon injury model together with the mechanical loading device provide a new tool to investigate the mechanical boundary conditions suitable for treating different types of tendon disorders.The findings from the current study points towards the significant contribution of PRP and mechanical loading to the healing process in tendons and could serve as a promising starting point for developing integrated therapeutic modalities to improve the quality and speed of recovery from tendon injury.</p

Platelet rich plasma and mechanical loading in regenerative tendon repair

Tendon injuries and tendinopathy are a growing problem in the aging but physically active population as well as athletes. Tendons have highly ordered matrix and undergo complex changes during the remodelling phase of tendon healing. Moreover, anaerobic metabolism and poor vascular network contribute to slow adaptation of tissue to the remodelled matrix which consequently results in slow and compromised healing. Such a destitute and slow healing process necessitates development of new and effective therapies and to combine therapies to obtain possibly synergistic effects.Addressing this clinical requirement, the work presented in this thesis investigates the role of two emerging treatment options, platelet rich plasma (PRP) and mechanical loading, on tendon healing.The effects of PRP, a rich autologous source of growth factors, on tendon cells was studied by modelling important stages of tendon healing in vitro. Key parameters such as cellular migration, chemotaxis, viability and senescence were investigated by means of different culturing and staining techniques together with microscopic analyses.PRP significantly increased migration and chemotaxis in human primary tenocyte culture. Moreover, PRP protected human tenocytes against challenging environments created by known tendon damaging drugs, dexamethasone and ciprofloxacin, as well as the injury relevant condition of hypoxia.Concurrently, an in vitro rat tail tendon injury model and static loading device was developed to assess the effect of static mechanical loading and PRP on the biochemical and biomechanical properties of tendon at the tissue level. This in vitro system was also used to investigate the synergistic effects of PRP and mechanical loading on tendon healing. Both PRP and mechanical loading helped to improve the biomechanical and biochemical properties of damaged tendon in vitro.In conclusion, the positive effects of PRP on key cellular parameters such as cell survival, migration and chemotaxis and also mechanical and biochemical properties of tendon tissue make it an important option for faster and less invasive tendon treatment. Additionally, an in vitro tendon injury model together with the mechanical loading device provide a new tool to investigate the mechanical boundary conditions suitable for treating different types of tendon disorders.The findings from the current study points towards the significant contribution of PRP and mechanical loading to the healing process in tendons and could serve as a promising starting point for developing integrated therapeutic modalities to improve the quality and speed of recovery from tendon injury.</p

The regulatory ancestral network of surgical meshes

<div><p>Background</p><p>All surgical meshes entering the U.S. market have been cleared for clinical use by the 510(k) process of the Food and Drug Administration (FDA), in which devices simply require proof of “substantial equivalence” to predicate devices, without the need for clinical trials. However, recalled meshes associated with adverse effects may, indirectly, continue to serve as predicates for new devices raising concerns over the safety of the 510(k) route.</p><p>Methodology</p><p>Here we assess the potential magnitude of this problem by determining the ancestral network of equivalence claims linking recently cleared surgical meshes. Using the FDA website we identified all surgical meshes cleared by the 510(k) route between January 2013 and December 2015 along with all listed predicates for these devices. Using a network approach, we trace the ancestry of predicates across multiple generations of equivalence claims and identify those meshes connected to devices that have since recalled from the market along with the reason for their recall.</p><p>Conclusions</p><p>We find that the 77 surgical meshes cleared between 2013 and 2015 are based on 771 interconnected predicate claims of equivalence from 400 other devices. The vast majority of these devices (97%) are descended from only six surgical meshes that were present on the market prior to 1976. One of these ancestral meshes alone, provided the basis of 183 subsequent devices. Furthermore, we show that 16% of recently cleared devices are connected through equivalence claims to the 3 predicate meshes that have been recalled for design and material related flaws causing serious adverse events. Taken together, our results show that surgical meshes are connected through a tangled web of equivalency claims and many meshes recently cleared by the FDA have connections through chains of equivalency to devices which have been recalled from the market due to concerns over clinical safety. These findings raise concerns over the efficacy of the 510(k) route in ensuring patient safety.</p></div

An in vitro scratch tendon tissue injury model: effects of high frequency low magnitude loading

The healing process of ruptured tendons is suboptimal, taking months to achieve tissue with inferior properties to healthy tendon. Mechanical loading has been shown to positively influence tendon healing. However, high frequency low magnitude (HFLM) loads, which have shown promise in maintaining healthy tendon properties, have not been studied with in vitro injury models. Here, we present and validate an in vitro scratch tendon tissue injury model to investigate effects of HFLM loading on the properties of injured rat tail tendon fascicles (RTTFs). A longitudinal tendon tear was simulated using a needle aseptically to scratch a defined length along individual RTTFs. Tissue viability, biomechanical, and biochemical parameters were investigated before and 7 days after culture . The effects of static, HFLM (20 Hz), and low frequency (1 Hz) cyclic loading or no load were also investigated. Tendon viability was confirmed in damaged RTTFs after 7 days of culture, and the effects of a 0.77 ± 0.06 cm scratch on the mechanical property (tangent modulus) and tissue metabolism in damaged tendons were consistent, showing significant damage severity compared with intact tendons. Damaged tendon fascicles receiving HFLM (20 Hz) loads displayed significantly higher mean tangent modulus than unloaded damaged tendons (212.7 ± 14.94 v 92.7 ± 15.59 MPa), and damaged tendons receiving static loading (117.9 ± 10.65 MPa). HFLM stimulation maintained metabolic activity in 7-day cultured damaged tendons at similar levels to fresh tendons immediately following damage. Only damaged tendons receiving HFLM loads showed significantly higher metabolism than unloaded damaged tendons (relative fluorescence units —7021 ± 635.9 v 3745.1 ± 641.7). These validation data support the use of the custom-made in vitro injury model for investigating the potential of HFLM loading interventions in treating damaged tendons

The ancestral device network of the recalled devices Composix Kugel Mesh (K003323) and PROCEED Trilaminate SurgicalMesh (K031925).

<p><b>+</b> Shows devices with more than 2 recalled predicates.</p

Public availability of clinical and scientific evidence for the meshes that have led to over 100 off-spring devices.

<p>Public availability of clinical and scientific evidence for the meshes that have led to over 100 off-spring devices.</p

The total number of descendent devices connected to each ancestral predicate (n = 400) by chains of substantial equivalency.

<p>Ancestral predicates are grouped according to the time period in which they entered the market (bar color) to highlight that the skewed distribution in the number of descendent devices is not an artefact of the time available for ancestral predicates to accumulate descendants. Mersilene Surgical Mesh had the largest number of descendent devices and is highlighted (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0197883#pone.0197883.g003" target="_blank">Fig 3</a> for the ancestral history of this device).</p

The ancestral device network of Mersilene Surgical Mesh manufactured by Ethicon Inc.

<p>Mersilene Mesh has led to 183 descendent devices. Devices in the ancestral network that have since been recalled for ‘design and material related flaws’ (n = 2) are highlighted in red. Devices that are descended from recalled devices by substantial equivalency chains (n = 12) are highlighted in yellow (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0197883#pone.0197883.s002" target="_blank">S2 Data</a> for devices).</p

The regulatory ancestral network of surgical meshes - Fig 1

<p>a) The number of ancestral predicates underlying surgical meshes cleared by the FDA between 2013–2015. Each surgical mesh has on average 33 ancestral predicates, but the number of ancestors differs widely between meshes b) the number of devices in our dataset (n = 477) cleared by the FDA each year from prior to the 1976 Medical Device Amendment Act 2015 (i.e. < 1976) to 2015.</p