Table 1.

Domains and Description for the Appraisal of the Risk of Bias for In Vitro and In Vivo Studies Using Risk of Bias Assessment Tool for Non-Randomized Studies (RoBANS).

Domain	Description for In Vitro and In Vivo Studies
Selection of chondrocytes or animals	Selection bias caused by inadequate selection of cells and animal participants. In in vitro studies, selection of chondrocytes cells should be performed from commercially available cell lines or from cartilage samples collected from animals. In both cases, chondrocytes should be obtained from hyaline cartilage. Chondrocytes should be isolated from more than one animal with same characteristics (type, race, weight, and age) from the same anatomical site. Ideally, allocation of cells would be randomized. Chondrocytes phenotype after isolation protocol should be confirmed for specific chondrogenic surface markers (e.g., CD44, CD49, CD73, CD90, CD105, CD151, and CD166) and/or for chondrogenic markers (e.g., COL II, ACAN, SOX-9).16 -18 Control and intervention groups should be clearly defined. In in vivo studies, animal participants with same characteristics should be selected. Ideally, allocation of animals would be randomized. Controls and intervention groups should be clearly described.
Confounding variables	Selection bias caused by inadequate confirmation and consideration of confounding variables. For in vitro studies, cartilage should be collected from the same anatomical sites and isolated chondrocytes should have the same viability and count among groups. Studies should implement the same isolation protocol and same protocol for establishing the primary cell culture(s). The number of cell passages should be the same for all experimental groups and should not be too high, since chondrocytes lose their phenotype with increasing number of passages. 19 The culture medium volume should be the same for all wells among experimental groups to avoid different radiation scattering between groups. Same experimental conditions should be guaranteed for both control and intervention groups (e.g., humidity, CO2 and temperature conditions). In vivo studies should be consistent regarding the animal model, race, weight and age, ratio of male/female among experimental and control groups and number of animals per group. Animal participants should be housed under the same conditions, light cycles time and temperature. The animal euthanasia and OA induction method should be clearly described and the same among groups. The day of OA induction should be clearly defined and the recovery time before interventions should be performed for all experimental and control groups.
Exposure of measurement	Performance bias caused by inadequate measurement of exposure. Measurement techniques should be adequate and well-established for the specific outcomes that studies are assessing, and their measurement protocol should be clearly described to allow for replication. Semiquantitative and/or qualitative analysis should be performed by two independent observers to ascertain interoperator reliability.
Blinding outcome assessment	Detection bias caused by inadequate blinding of outcome assessment. Outcome assessor and/or data analysist not blinded to group (i.e., intervention vs. control). For quantitative analyses, the blinding of outcome assessor and/or data analyst was not considered necessary. Otherwise (semiquantitative and qualitative analyses), blinding was required.
Incomplete outcome data	Attrition bias caused by inadequate handling of incomplete data outcome. Missing data in >5% of outcome variables.
Selective outcome reporting	Reporting bias caused by selective outcome reporting. Based on reporting of the collected/assessed outcomes and multiple subgroup analyses.
Planning and implementation of interventions*	Performance bias caused by inadequate planning and implementation of interventions. LT should be performed by the same operator and parameters should be clearly described to allow for replication. The application mode such as distance to cells/skin, scanning or skin contact method, angle of light source should be clearly described. Type of light source, operating mode (continuous or pulsed) and number of actuators should be defined in each experimental group. LT parameters should be stated, as well as the number of LT sessions and the number of irradiated points. A temperature control should be performed during interventions since LT should not induce a temperature rise in tissues or cells.4,20 Previous calibration and/or power parameters control during experiments should be performed. In in vitro studies, the radiation scattering between wells in same well plate must be considered during irradiation. Blinding of personnel or testing source (cells/animals) is not possible. In these interventions, the LT parameters are pre-determined, the personnel who applies the intervention (LT) cannot change the intervention or affect the outcomes. Thus, we did not judge performance bias related to blinding of personnel or testing source.
Funding bias a	Funding bias caused due to financial sponsoring or conflict of interest. Conflict of interest from study authors and/or sponsoring of industry.

CD44, CD49, CD73, CD90, CD105, CD151, and CD166, antigen molecules at cells surface; COL II, collagen type II; ACAN, aggrecan; SOX-9, SRY-box transcription factor 9; OA, osteoarthritis; LT, light therapy.

^aDomains added to the validated RoBANS tool to adjust to the context of this systematic review.