Bridge-enhanced ACL repair: A review of the science and the pathway through FDA investigational device approval

Abstract

Injuries to the anterior cruciate ligament (ACL) are currently treated with replacement of the torn ligament with a graft of tendon harvested from elsewhere in the knee. This procedure, called "ACL reconstruction," is excellent for restoring gross stability to the knee; however, there are relatively high graft failure rates in adolescent patients (Barber et al. in Arthroscopy 30(4):483-491, (2014); Engelman et al. in Am J Sports Med, (2014); Webster et al. in Am J Sports Med 42(3):641-647, (2014)), and the ACL reconstruction procedure does not prevent the premature osteoarthritis seen in patients after an ACL injury (Ajuied et al. in Am J Sports Med, (2013); Song et al. in J Sports Med 41(10):2340-2346, (2013); Tourville et al. Am J Sports Med 41(4):769-778, (2013)) .Thus, new solutions are needed for ACL injuries. Researchers have been investigating the use of scaffolds, growth factors and cells to supplement a suture repair of the ACL (bridge-enhanced repair; also called bio-enhanced repair in prior publications). In this paper, we will review the varied approaches which have been investigated for stimulating ACL healing and repair in preclinical models and how one of these technologies was able to move from promising preclinical results to FDA acceptance of an investigational device exemption application for a first-in-human study.

Figure 1

The distal femur for four porcine knees at one year after ACL transection and either no further treatment (ACLT), ACL reconstruction with a bone-patellar tendon-bone allograft (ACLR), bridge-enhanced repair using a scaffold loaded with autologous blood (BE-Repair) and an ACL reconstruction enhanced with a scaffold loaded with autologous blood (BE-ACLR). The medial femoral condyle in the ACLT and ACLR groups have breakdown of the articular surface consistent with post-traumatic osteoarthritis (black arrows). These changes are seen in the same location as seen in human patients after ACL injury, even with reconstruction. In the bridge-enhanced groups, less damage is noted, suggesting a potential beneficial effect of adding a scaffold loaded with autologous blood to an ACL repair or reconstruction (adapted from Murray and Fleming, AJSM 2013).

Figure 2

Flow chart listing steps to successfully get through an IDE application for a medical device at the FDA.

Figure 3

Example of a section of a production Failure Mode Effect Analysis (PFMEA). This document serves to record all the potential causes of failure the design and manufacturing team can think of and to record the methods that will be used to reduce this risk. Abbreviations: BAR (Broadly Acceptable Region). ALARP (As Low As Reasonably Practicable). INT (Intolerable). Severity score ranges from 1 to 10, with 1 being the least severe and 10 being the most severe. Occurrence ranges from 1 to 10 as well, with 1 being infrequent risk of occurring and 10 being frequent likelihood of failure to occur. Rating is the product of severity and occurrence and is assigned a classification of either BAR, ALARP, or INT. Higher ratings between 40 −100 are not considered acceptable and classified as INT. Risks rated between 16 and 36 may be acceptable, providing there is adequate justification regarding risk/benefit ratio and are classified as ALARP. Risks rated below 16 are rated as BAR.

Figure 4

Sample Template for a Process Specification Document. These documents are used for each step of the processing - most manufacturing procedures will have several of these documents for each manufacturing process. At the top, the process specification number and revision level are listed. The document contains the objective, defect awareness, required materials and specific process steps, as well as associated signatures once the process specification is defined.

Figure 5

Sample Template for Production Log document. These documents are used to document the performance of any step in the process, be it manufacturing or device testing. At the top, the number of samples tested and the specific numbers are listed. The solutions used in the testing are then specified in the next section, followed by the method for the assay or production step. The results of the assay or production step are then recorded in the results section. The production log template is signed before use.

Figure 6

Sample Production Router document. In the Production Router, the equipment used in each step is identified and inspected for date of calibration and proper function. The lot number of each chemical used in the processing is recorded in the next section and the technician performing the step signs and dates the form each time a step is completed.