Biomodulating healing after arthroscopic rotator cuff repair: the protocol of a randomised proof of concept trial (BIOHACK)

Abstract

Purpose/introduction

Over the last decades, there has been increasing interest in biological stimulation or bioaugmentation after rotator cuff repair. So far, there is no consensus on the appropriate composition of biologicals or which patients would benefit most, and moreover, these biologicals are often expensive. However, there are other, non-pharmacological strategies that are also believed to achieve biological stimulation. This randomised controlled trial evaluates the possible cumulative effect of pragmatic application of cryobiomodulation, photobiomodulation and electrobiomodulation—collectively called biomodulation—on the bone-to-tendon healing process after rotator cuff repair.

Methods

In this randomised, controlled proof of concept study, 146 patients undergoing arthroscopic repair of a full thickness posterosuperior or anterosuperior rotator cuff tear will be 1:1 randomly assigned to either a control group or to the additional biomodulation protocol group. The adjuvant biomodulation protocol consists of seven self-applicable therapies and will be administered during the first 6 weeks after surgery. Primary outcome will be healing of the rotator cuff as evaluated by the Sugaya classification on MRI at 1-year postoperatively.

Ethics and dissemination

This study has been accepted by the National Ethical Review Board CPP Sud-Est IV in France and has been registered at Clinicaltrials.gov. The results of this study will be published in a peer-reviewed journal.

Trial registration number

NCT04618484.

Strengths and limitations of this study

• This study is the first to evaluate the effect of non-pharmacological bioaugmentation after rotator cuff repairs.

• The study is a randomised controlled trial, minimising bias and providing a higher level of evidence for assessing the effect of bioaugmentation.

• The research protocol provides a pragmatic protocol to implement non-pharmacological strategies for improving the bone-to-tendon healing process after rotator cuff repair.

• Due to the nature of the intervention, a double-blinded approach is not possible for this study.

Introduction

With the rising incidence of rotator cuff repairs and the previously existing high financial pressure on global healthcare, there is an unprecedented need for improving cost-effective and pragmatic treatment strategies.^1–3 At 2 years follow-up, there is no clear advantage to surgery as operated patients have comparable outcomes to those treated conservatively,^{4 5} but in the long term operated patients show better results.⁶ However, recent meta-analyses show that between 22% and 50% of the patients who undergo rotator cuff repair present with a recurrent tear.^7–10 Most of the recent evidence suggests that this subgroup of patients commonly has clinically significant worse outcomes.^11–13 Therefore, there is a continuous need to investigate innovative cost-effective and pragmatic approaches to improve healing rates.

Over the last decades, there has been increasing interest in biological stimulation or bioaugmentation in order to improve tendon-to-bone healing, which has led to the development of biological implantable devices and regenerative supplements like stem cells, PRP and other growth factors.^{14 15} Consistent with most preclinical studies on the effect of biologicals on tendon healing, the latest meta-analyses on the effect of Platelet Rich Plasma (PRP) seem to suggest increased tendon healing after surgical repair.^16–18 However, no benefits were documented in terms of clinical outcomes. These inconsistent results, the high heterogeneity of injected products and generally high production and therefore usage costs of biologicals, contribute to the current lack of consensus on the ideal composition of biologicals.^{17 19} However, there are other, non-pharmacological strategies that are also believed to achieve biological stimulation. These non-pharmacological therapies might offer viable alternatives because of their easy application, little side effects and low costs.

Examples of non-pharmacological strategies are cold therapy (cryobiomodulation), exposure to a specific spectrum of electromagnetic radiation (photobiomodulation) and electrical microcurrent therapy (electrobiomodulation). Icing or cold therapy is commonly used after injury and surgery due to its analgetic effect and ability to reduce swelling. In their 2017 systematic review, Dickinson et al described cryotherapy as a simple, cost-effective way to improve outcomes after rotator-cuff repair.²⁰ Yoon et al showed evidence of pain relief by postoperative far-infrared light application, which could potentially lead to an increase in patient-reported outcomes and satisfaction.²¹ Blue light is thought to indirectly benefit rotator cuff healing by stimulating the body’s internal circadian rhythm.²² Even as research towards the circadian clock in tendons is still limited,²² there is increasing evidence that bone metabolism is strongly dependent on the cells’ internal circadian rhythm.^{23 24} Previous research has proven feasibility and efficacy of different blue light filters.²⁵ Grounding, or earthing, is a simple method where a conductive connection is formed between the skin of the patient and the ground. The available evidence reports anti-inflammatory effects, increased wound healing and faster muscle recovery after exercise.^{26 27} Even though theoretical explanation of the underlying mechanism faces several difficulties, the low cost and easy application make grounding an interesting non-pharmacological therapy.

Current evidence on the efficacy of these treatment strategies shows positive effects on pain, function and range of motion but is generally considered weak, as it is based on small, heterogenous studies.^{20 28} More importantly, previous research has rarely focused on the effects on tendon healing but rather on the effect on previously mentioned outcomes. Therefore, there is great need for large, objectively validating studies on the efficacy of these non-pharmacological therapies.

Aim and hypothesis

Aim of this study

The aim of this study is to evaluate the possible cumulative effect of pragmatic application of cryobiomodulation, photobiomodulation and electrobiomodulation—collectively called biomodulation—on the bone-to-tendon healing process after rotator cuff repair.

Null hypothesis

The pragmatic application of a supplementary biomodulation rehabilitation protocol does not significantly decrease the chance of retear after rotator cuff repair, defined as Sugaya type 4–5.

Methods and analysis

Methods

In this randomised, controlled proof of concept study, patients undergoing arthroscopic repair of a full thickness posterosuperior or anterosuperior rotator cuff tear will be 1:1 randomly assigned to either a control group or to the additional biomodulation protocol group. Patients are identified during consultation or selected using data from the electronic patient files and approached for participation prior to surgery, based on the inclusion and exclusion criteria presented in box 1. All screened patients who were classified as non-eligible or refused will be registered and included in the flow diagram. The informed consent form is signed before participation by both the patient and research doctor and included as online supplemental file 1. For both groups, repair will be performed in beach chair position by one of four participating resident surgeons using a knotted suture bridge technique, and immobilisation will be performed with a standard abduction sling for 6 weeks allowing for passive pendulum exercises only. The 1-year postoperative MRI will be graded by an independent radiologist who will be blinded to the treatment arm of the patient. This study will be performed in the Clinique Générale Annecy, Annecy, France.

Box 1. Inclusion and exclusion criteria.

Inclusion criteria

• Patient is over 18 years old.

• Patient presents with a symptomatic full-thickness tear as diagnosed preoperatively on ultrasound, arthro-CT or MRI.

• Absence of significant muscle atrophy or fatty infiltration of the affected tendon exceeding stage II of the Goutallier classification³⁶

Exclusion criteria

• Partial rotator cuff tear or other shoulder injury

• Planned concomitant procedures other than subacromial decompression, acromioclavicular joint resection or biceps tenodesis/tenotomy

• Irreparable rotator cuff tear

• Patients who present with cartilage lesions greater than stage II of the Outerbridge classification (≥15 mm diameter) on preoperative x-ray³⁷

• Patient presenting with a known comorbidity that could affect the outcome of surgery (cervical radiculopathy, polyarthritis, neurological disease of the upper limb)

• Patient not able to give informed consent

Postrandomisation exclusion

Patients who will be found to have one or more exclusion criteria after randomisation will be excluded from the final analysis. This includes cases where intraoperative findings will prove patients ineligible, or the surgery will be cancelled after inclusion.

Statistical analysis

A recent previous study found a probability of retear defined on MRI at 1 year after arthroscopic double row rotator cuff repair of 0.3 (retear rate 30%).¹² If the true probability of exposure among patients with biomodulation is 0.1 (retear rate of 10%), 59 analysed patients per group are necessary to reject the null hypothesis (power, 80%). The type I error probability associated with this test of the null hypothesis is 0.05. An uncorrected χ² statistic will be considered for evaluation of the null hypothesis. To compensate for an eventual loss of recruited patients during follow-up, the number of patients is increased by approximately 25% to a total of 146 (73 patients in each group).

Data distribution will be assessed by visual inspection of histograms and the Kolmogorov-Smirnov test. Independent t-tests or non-parametric Mann-Whitney U tests will be used to compare continuous variables between the study and control groups. Paired t-tests or non-parametric Wilcoxon signed-rank tests will be used to compare scores between two time points. Categorical data will be assessed with Fisher exact or χ² tests. Results will be reported for both intention-to-treat analysis and per-protocol analysis. Data will be analysed with Excel (Microsoft Office 2013) and SPSS software (PAWS Statistics V.23; IBM). Statistical significance is set at the conventional p<0.05 (two-sided).

Stratification and allocation

Patients will be stratified over three subgroups based on tendon retraction according to the Patte classification on preoperative imaging.²⁹ Permutated block randomisation with a block size of 4 will be used to allocate patients in equal proportion to the treatment or control group by using Study Randomizer (Phase Locked Software, Wageningen, The Netherlands).

Outcomes and follow-up

Primary and secondary outcomes are summarised in box 2.

Box 2. Primary and secondary outcomes.

Primary outcome

• Primary outcome will be healing of the rotator cuff as evaluated by the Sugaya classification on MRI at 1 year postoperatively.³⁸

Secondary outcomes

• Patient reported outcome measures: Pain, reported as average of reported pain during movement, at rest and at night, measured by a Numeric Rating Scale from 0 to 10; and the Auto-Constant Score, Subjective Shoulder Value, the American Shoulder and Elbow Surgeon Score^39–41

• Active range of motion: Degrees of forward flexion, abduction, internal rotation and external rotation (90° elbow flexion, 0° and 90° abduction)

• Self-reported daily compliance to the different components of the biomodulation protocol in the first 6 weeks after surgery

• Postoperative complications in the first year after surgery

Follow-up and compliance

All secondary outcomes will be measured preoperatively, as well as 6 weeks, 3 months, 6 months and final follow-up will be at 1 year postoperatively and will be registered using Follow (Follow Health, Rennes, France, CNIL D1898364). All study participants in the intervention group will receive a logbook to fill out daily compliance with the biomodulation protocol, which will be recuperated at the 6 weeks follow-up. A flow diagram of the study is included as online supplemental file 2.

Rehabilitation protocol

The standard rehabilitation protocol for both groups consists of immobilisation in a sling for 6 weeks and standard pendulum exercises only, followed by physiotherapy following a standard protocol for all patients.

The adjuvant biomodulation protocol consists of seven self-applicable therapies and will be administered during the first 6 weeks after surgery. During the inclusion, patients in the intervention group are provided with clear instructions on how to perform all possible therapies. As passive cryotherapy (incorporated in the sling) can be performed during light activities, the maximal active rehabilitation burden is estimated at 3×30 min/day. The protocol consists of the following.

Cryobiomodulation

Application of ice packs three times daily

Patients will be provided with an extension to the standard immobilisation sling that can hold two ice packs (FIRSTICE ÉPAULE, Sober Ezy-Wrap). Patients will be instructed how to place and replace the ice packs independently after surgery. The icepacks are stored frozen and therefore effective immediately after the instruction. After placement, the ice packs should remain on the shoulder for at least 20 min, but due to the properties of the artificial ice, the ice packs can safely remain on the shoulder for unlimited time and will remain cold for over 1 hour.³⁰

Optional daily thorax immersion in a bath with tap-cold water

Second, regional cryotherapy can be performed by submerging the thorax for 5–10 min into a tap-water cold bath (recommended, 10–12°C or colder). Early submersion of the operated shoulder and healing portal wounds—3–5 days postoperative or as soon as they become unproductive—has been shown to be safe in on arthroscopic rotator cuff repair, with no increased risk of infection even in public pool facilities.³¹

Photobiomodulation

Daily 20-min sunlight session for ultraviolet (UV) light

The UV sunlight session consists of upper body exposure to the sun for 20 min during the 2 hours around solar noon, which is commonly around 12:30 and determined individually during the inclusion and instruction session depending on the time of year. Participants are encouraged to use the open-source smartphone application Dminder (Ontometrics, Los Angeles, California, USA) estimate, track and optimise their vitamin D levels and individual sunburn risk by filling out determinant factors including skin tone, age, weight and amount of skin exposed. Patients are always advised to apply sunscreen without transmission metals content on the portal scars³² when exposed to midday sun.

Up to two daily 20-min sunlight sessions for infrared (IR) and near-IR light

The 20-min sunlight sessions for the combination of IR and near-IR light also consist of exposing the full upper body and are possible twice every day, during the 2 hours after dawn (sunrise) and the 2 hours before dusk.

Reduction of artificial blue light exposure

All patients are informed of different possibilities to diminish the influence of artificial light at night. All modern screen devices are equipped with blue light filtering software. On Apple OS devices and laptops, patients are advised to use the integrated night-shift setting from sunset to sunrise. On Google/Android devices, patients are advised to download the open-access application Twilight (Urbandroid) and programme the filter to automatically activate from sunset to sunrise. Patients are instructed to wear the red-lens glasses (156×57×115 mm red, Fuyuanda Optical Technology, Xiamen, China) when exposed to other artificial light sources, particularly when watching television.^{33 34} The spectral filtering properties of glasses have been confirmed using a spectrometer (Hopoocolor, OHSP350S 350–950 nm PPFD TM-30); results are shown in figure 1.

Figure 1.

Spectrometry results of (A) normal lighting with open window and (B) placing spectrometer directly behind glasses. Spectrometer: Hopoocolor, OHSP350S 35 PPFD TM-30. Glasses: Optical 350–950 nm.

Electrobiomodulation

Generating natural terrestrial conduction, or grounding, by bare foot walking

Bypass of all rubber soles by placing conduction strips in shoes connecting the heel with the ground

For all non-leather shoe material such as rubber, each participant will be provided a conductive shoe strap, universally compatible (Erthe 3.0 PRJ20, Australia). When at home or during the photobiomodulation sessions, it is recommended to bare the feet from any static material to stimulate conduction.

Ethics and dissemination

This study has been accepted by the National Ethical Review Board CPP Sud-Est IV in France and has been registered at Clinicaltrials.gov. The results of this study will be published in a peer-reviewed journal.

Patient and public involvement

Patients and the public were not involved in the making of this protocol.

Current status

Currently, the inclusion phase is ongoing and is expected to continue until mid-2023. The follow-up phase will last until 1 year after the final inclusion; therefore, final results are expected to be submitted for publication towards the end of the year 2024.

Discussion

Design of study

Due to the nature of the intervention, a double blinded study design will not be possible. However, the evaluating radiologist who will assess the rotator cuff integrity is not aware of the assigned treatment arm. Therefore, the study design is single blinded.

Because the biomodulation protocol will commence the first day after surgery, inclusion has to take place in advance. Consequently, a limitation of this study is that intraoperative findings cannot be used to confirm inclusion or exclusion criteria. Inappropriately included patients will have to be excluded from the analysis concerning the main outcomes; however, they might still be included in analysis on compliance to the protocol or adverse events caused by the protocol.

Design of protocol

The protocol was designed to be as pragmatic and cost-effective as possible: during the first 6 weeks after arthroscopic rotator cuff repair, most patients are absent from work, unable to drive, considered non-productive, immobilised in sling and do not yet engage in physiotherapy. The budget per patient is included in online supplemental file 3. Patients have shown to highly appreciate the opportunity for so-called ‘patient empowerment’, enabling them to potentially voluntarily optimise their health condition with modalities such as cryotherapy.³⁵ The protocol is a combination of different treatment strategies, none of which have been previously investigated in relation to retear of the rotator cuff. The purpose of this wide approach is to enlarge the likelihood of demonstrating efficacy of non-pharmacological therapies altogether, as well as further stimulating the patient empowerment described earlier.

Data availability statement

Due to privacy reasons, individual patient data will not be available to the public.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).

Ethics approval

Case number CPP: CPPSE 4 2021-05-002/BIOHACK/2021-A01239-32/CPP 21.05.25.66932.