Effectiveness of Stromal Vascular Fraction (SVF) and Platelets Rich Plasma (PRP) in Osteoarthritis and Tendinopathy (SPOT)

Effectiveness of Stromal Vascular Fraction (SVF) and Platelets Rich Plasma (PRP) in Osteoarthritis and Tendinopathy

Effectiveness of Stromal Vascular Fraction (SVF) and Platelets Rich Plasma (PRP) in Osteoarthritis and Tendinopathy: Study Protocol for a Phase III, Prospective, Randomized, Controlled Multi-center Study: (SPOT Study).

In a multi-centric, randomized, triple-blind controlled trial, 195 patients will be separated in 2 subgroups: 130 individuals with osteoarthritis and 65 with tendinopathies. The mian question to answer are the effect of SVF on : The clinical improvenent The cartilage thickness evolution in case of osteoarthritis The tendon healing in case of thendinopathy Patients will receive an initial single PRP or PRP + SVF injection followed by one- and two-months PRP doses. In parallel, they will beneficiate of a proper rehabilitation plan with active physical therapies.

Background: Osteoarthritis and tendinopathies are two frequent diseases with a high social and individual impact. Both have multifactorial etiology and the development of therapeutic options is a public health priority. Osteoarthritis is the most common joint disease, and more than 30% of sports-related injuries have a component of tendinopathy. Most common conservative treatments for osteoarthritis treatment include painkillers, active physical therapies, orthotics, infiltrations of corticosteroids, hyaluronic acid (HA), and platelet-rich plasma (PRP). PRP may be beneficial in both tendinopathy and osteoarthritis by interfering with catabolic and inflammatory events and by subsequently promoting anabolic responses. Activation of PRP releases biologically active components, including platelet-derived growth factor (PDGF), transforming growth factor-β (PGF-β), type I insulin-like growth factor (IGF-1) and vascular endothelial growth factor (VEGF). These proteins are responsible for a range of critical tissue healing roles such as chondrocyte and mesenchymal stem cells proliferation, bone and vessel remodeling, inflammatory modulation and collagen synthesis. For osteoarthritis, an improvement of clinical outcomes is clearly established, presumably associated with the chondroprotective effect of PRP. Nevertheless, an in-vivo effect on human cartilage regeneration is not yet demonstrated despite the numerous studies approaching the subject. Most common conservative treatments for tendinopathies include painkillers, bracing, active physical therapies, extracorporeal shockwave therapy, other specific therapies (cryotherapy, red light therapy, topical glycerol trinitrate, PRP and tendon lengthening. Clear clinical benefits are currently demonstrated with active exercises and extracorporeal shockwave therapies. Tendon needling, also known as tendon fenestration or percutaneous needle tenotomy, intends to disrupt the chronic inflammatory and degenerative processes through localized bleeding, fibroblastic proliferation, and organized collagen synthesis. The intervened tendon can also lengthen in some cases. Preclinical models elucidated how injected Adipose Derived- Mesenchymal Stem Cells (AD-MSC) coordinate the cartilage regeneration process through paracrine mechanisms, producing cytokines and trophic bioactive factors that stimulate cellular proliferation, reduce inflammation, fibrosis, oxidative stress, and chondrocytes senescence. Stromal Vascular Fraction (SVF), a product from specific adipose tissue processing, contains mesenchymal stem cells, endothelial precursor cells, T regulatory cells, macrophages, smooth muscle cells, pericytes and preadipocytes. SVF extraction and injection techniques have been recently used as an alternative to harvest AD-MSC due to its logistic simplicity and feasibility in clinical practice. SVF injections produce a clinically significant effect on the treatment of knee osteoarthritis, and a possible improvement in cartilage quality. Promising results were observed in the Achilles tendon. This clinical trial aims to assess the clinical efficacy of SVF as adjuvant therapy to PRP on functionality and tissue regeneration on osteoarthritis and tendinopathies.

Multicentric randomized. Study participants will be split to osteoarthritis and tendinopathies subgroups. Randomization will be performed at a 1:1 ratio to either the intervention arm or the active comparator. Each block of 4 patients will be assigned to specific strata according to the pathology (osteoarthritis or tendinopathy) age (over or under 40), presence of either partial, full cartilage defects or full cartilage defects with bone deformation (osteoarthritis group) and tendon cross-section involvement greater or less than 50% (tendinopathy group).

This study is triple-blinded concerning (i) the participants during the intervention and throughout the study duration, (ii) the outcome assessor, and (iii) the statistician. In case of tendinopathy, an independent and blinded investigator will perform the tendon needling to patients in both study arms. The investigator in charge of the injections will be unblinded and therefore will not be assigned to outcomes assessment. Follow-up and outcome assessment will be identical for both arms.

Patients will receive a venepuncture to obtain PRP, and a lipoaspirate to obtain SVF. Then an ultrasonographic guided PRP+SVF injection will be performed. Patients will consecutively receive two monthly PRP injections. Patients in tendinopathies subgroup will besides undergo tendon needling concomitant to each injecetion.

Patients will receive a venepuncture to obtain PRP, and a sham lipoaspirate. Then an ultrasonographic guided PRP injection will be performed. Patients will consecutively receive two monthly PRP injections. Patients in tendinopathies subgroup will besides undergo tendon needling concomitant to each injecetion.

Procedure to prepare SVF: In the operations room and after aseptic technic, local anesthesia is applied in the liposuction incision site with lidocaine 1% without epinephrine subcutaneously. 60 ml of tumescent solution are injected. After 15-20 minutes waiting, 15 ml of lipoaspiration per side are recollected into a double syringe. This is centrifuged for 4 minutes at 2.500 rpm and the remaining fat is separated from the other fractions. Two 1.4 mm GEMS syringes are attached together, and fat is transferred at least 30 times from one syringe to the other. Syringe content is again centrifugated for 4 minutes. The oil is discarded and approximately 1.5ml SVF fraction remains.

Procedure to prepare PRP: 15 cm of peripheral blood obtained by venipuncture are centrifugated at 5000 RPM during 5 minutes. Using PRP Arthrex kit platelets poor plasma is discarded and 1-3 mm of PRP are ready to be injected

The absolute difference (changes from baseline to other time points) between the treatment and control groups on the Single Assessment Numeric Evaluation (0 meaning the poorest function to 100 meaning an optimal function).

The absolute difference (changes from baseline to other time points) between the treatment and control groups on the Quick Disabilities of Arm, Shoulder, and Hand score for the superior member (0 meaning lower disability to 100 meaning most severe disability).

The absolute difference (changes from baseline to other time points) between the treatment and control arms on the Low Extremity Functional Scale for the inferior member (0 meaning lower disability to 80 meaning most severe disability).

The absolute difference (changes from baseline to other time points) between the treatment and control arms on the Visual Analogue Scale (VAS) on a 0 to 10 scale. 0: no pain, 10: maximal pain

The absolute difference (changes from baseline to other time points) between the treatment and control arms on the Single Assessment Numeric Evaluation (SANE). From 0% functional to 100% being normal function.

The absolute difference (changes from baseline to other time points) between the treatment and control arms on the Western Ontario McMaster Universities Osteoarthritis Index on knee osteoarthritis cases. From 0 to 96, being 0: no limitation, 96: extreme limitation

The absolute difference between the treatment and control arms on Return to work in days since treatment

The absolute difference between the treatment and control arms on the Return to sport in days since treatment

The absolute difference (changes from baseline to other time points) between the treatment and control arms on the Affected cross-sectional tendon surface in mm2 on ultrasound

The absolute difference (changes from baseline to other time points) between the treatment and control arms on Affected tendon quality with elastography (difference in kilopascals from the healthy side) on ultrasound

The absolute difference (changes from baseline to other time points) between the treatment and control arms on Ultrasonographic doppler reaction judged as "absent", "minimal", "less than 1/3 of the affected area", "1/3-2/3 of the affected area" or "more than 2/3 of the affected area".

The absolute difference (changes from baseline to other time points) between the treatment and control arms on tendon tear size evolution from baseline in mm3

The absolute difference (changes from baseline to other time points) between the treatment and control arms on Affected cartilage quality on MRI using Area Measurement And Depth Underlying Structures (AMADEUS) score. (0 worst, 100 best)

Number of Participants with concomitant diseases (diabetes Miletus, dyslipidemia, arterial hypertension, osteopenia, osteoporosis, presence of rheumatologic disease, renal failure, and other relevant comorbidity)

Inclusion Criteria: Informed Consent as documented by signature (Appendix Informed Consent Form) Age older than 16 years old, Symptomatic osteoarthritis of the hip, knee, ankle, elbow, shoulder confirmed by MRI or symptomatic tendinopathy confirmed by ultrasonography, Failure of first-line conservative management in the last 3 months including medical or infiltrative treatment, orthotics use, active rehabilitation plan, adaptation of sports and work habits. Exclusion Criteria: Patient is familiar with the lipoaspiration process In case of tendinopathy: significant impingement according to investigator's judgement Subacromial impingement of the supraspinatus tendon, Haglund disease with erosion of the anterior part of Achilles tendon Significant disease of the contralateral member with a function evaluated with SANE score below 80% In case of osteoarthritis: microcristalline disease (i.e. gout, pseudogout), Active inflammatory rheumatic disorders, Need of regular anti-inflammatory treatment (either NSAIDs or corticosteroids), Allergy to local anesthetics or epinephrin Bleeding disorders or current anticoagulation therapy Patients with decompensated renal failure, hepatic dysfunction, or severe pulmonary or cardiovascular disease, Patients with an immunocompromised status Women who are pregnant or intend to become pregnant during the study Inability to follow the procedures of the study, e.g., due to language problems, psychological disorders, dementia, etc. of the participant, Known or suspected non-compliance, drug, or alcohol abuse Previous enrollment into the current study, Participation in another study with investigational drug or procedure within the 30 days preceding and during the present study Enrollment of the investigator, his/her family members, employees, and other dependent persons If a bilateral disease is present and both sides require either the experimental or the control intervention, only the most symptomatic side will be studied.

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