Biologic agents to optimize outcomes following ACL repair and reconstruction: A systematic review of clinical evidence

Clinical results + Del Torto M, 201520 Prospective comparative study (PRFM vs. Control) –

ACL recon.: hamstring tendon (RIGIDFIX® system and Bio-INTRAFIX™ system (DePuy)

PRFM was prepared using Cascade Medical Enterprises 2 tube kit (Cascade Medical Enterprises, Wayne, NJ)

PRFM-augmented: statistically significant clinical improvement at 24 months follow-up (p = .032)

IKDC score and Rolimeter arthromether: no difference between the two groups

28 patients (14 vs. 14) + Magnussen RA, 201342 Retrospective comparative study (PRP vs. Control) –

Decreased effusions at 10 ±4 days noted in the PRP group, but no difference at 8 ± 4 weeks

No differences in patient-reported outcomes were noted in the 58 patients with 2-year outcome data

58 patients (29 vs. 29) + Darabos N, 201125 Randomized trial (ACS vs. Control) –

ACL recon.: hamstring (30) or patellar tendon (32) - BioTransFix (Arthrex) or RigidFix (Mytek)\interference screw.

ACS was produced drawing venous blood into syringes containing pretreated glass beads. The injection regime of 4 injections on Day 0 (day of surgery), Day 1, Day 6, and Day 10

Clinical outcomes were better in patients treated with ACS at all data points; for all outcome parameters, with a statistically significant differences in the WOMAC stiffness subscale after 1 year

Decrease in IL-1b synovial fluid concentration more pronounced in ACS group

62 patients (31 vs. 31) + Vogrin M, 201033 Randomized trial (PRP vs. Control) –

ACL recon.: double-looped semitendinosus and gracilis tendon graft- bioabsorbable cross pins and bioabsorbable interference screw

PRP produced with Magellan system (Medtronic) and applied into the femoral and tibial tunnels as well as onto the graft itself

45 patients (22 vs. 23) Azcarate AV, 201434 Randomized trial (PRP vs. PRGF vs. Control) –

ACL recon.: patellar tendon allograft, transtibial technique—RigidFix (DePuy Mitek) and biodegradable (Byocril) interference screw.

PRP produced with a double-spin procedure using a standard centrifuge and applied covering the ligament

PRP produced following Anitua's technique (PRGF-Endoret® Technology) and applied injecting it into the graft before implantation, with the biocompatible fibrin applied into the tibial tunnel at the end of surgery

No significant differences in functional results at the final follow-up of 24 months

No statistically significant differences between the three groups in CRP 1 and VAS 24 h after surgery

No significant differences in the ROM, muscle torque, KT-1000 or IKDC score

The PRGF group showed a statistically significant improvement in swelling 24 h after surgery compared with the PRP and control groups

150 patients (50 vs. 50 vs. 50) − Vadala A, 201326 Randomized trial (PRP vs. Control) 40 patients (20 vs. 20) − Nin JR, 200943 Randomized trial (PRP vs. Control) –

ACL recon.: patellar tendon allograft—biodegradable cross pins and biodegradable interference screw.

Ligament covered with PRP (produced with standard centrifuge) and sutured over itself with PRP in its interior

The results did not show any statistically significant differences between the groups for inflammatory parameters, MRI appearance of the graft, and clinical evaluation scores after 18 months

100 patients (50 vs. 50) − Ventura A, 200541 Randomized trial (PRP vs. Control) –

ACL recon.: quadruple hamstring tendon graft— transcondylic fixation (BioTransFix) and tibial interference screw (BioRCI, Smith and Nephew)

PRP obtained according to the GPS Biomet-Merck technique (Biomet) and applied in femoral and tibial tunnels

20 patients (10 vs. 10) - Alentorn-Geli E, 2019 14 Controlled trial (adipose-derived regenerative stem cells (ADRC) vs. Control) ACL recon.: bone-patellar tendon-bone autograft—infiltrated with ADRC at the end of the procedure –

Both groups significantly improved the IKDC (p < .001 in both groups), Lysholm (p < .001 in both groups), Lequesne index (p < .001 in both groups), VAS for pain (p = .002 for the ADRC and p < .001 for the control group), and MRI scores (p < .001 in both groups) in the 12 months postop compared to baseline scores

There were no significant differences in the outcomes between groups across time (p > .05)

39 soccer players (20 vs. 19) + Berdis AS, 2019 44 Case series (PRP) ACL recon.: hamstring autograft tendon; ACL augmentation with PRP –

Biologic augmentation showed a decreased rate of ACL re-injury

Follow-up: 52 months. IKDC and Lysholm scores averaged 91 and 91; the average SANE score was 94. The KT-1000 side-to-side difference averaged 1.2 mm. The average time to complete physical therapy was 22 weeks, and 132 patients (92%) returned to their preinjury level of competition

143 patients (151 knees) Sözkesen S, 201830 Prospective study (PRP vs. control) ACL recon.: hamstring autograft without PRP. PRP administration into the femoral and tibial tunnel –

The patients were evaluated preoperatively and postoperatively with the IKDC score, Lysholm score, Tegner activity scale and a KT-1000 arthrometer device

No difference was seen between clinical examination results and the grading scales used

18 vs. 26 patients − Beyzadeoglu T, 2020 19 Cohort study (PRF vs. control) ACL recon.: semitendinosus tendon graft with growth factors and activated platelets –

PRF-treated grafts demonstrated lower MRI signal intensity and less fluid in the graft-tunnel interface as compared with controls

No clinical benefit of PRF could be demonstrated in clinical outcomes

Application of PRF led to superior graft integration and maturation in the proximal third of the ACL graft

44 patients (23 vs. 21) Tunnel enlargement + Starantzis KA, 201424 Randomized trial (PRP vs. Control) –

ACL recon.: quadrupled hamstrings graft—Crosspin Linvatec or Endobutton Linvatec and biodegradable interference screw (Linvatec) plus bone bridge suture anchoring

PRP (produced using the Biomet GPS III kit)

The morphology of the dilated tunnels was conical in both groups

There was a significant difference in the mid distance of the tunnels between the two groups 1 year after surgery

No significant difference in the Lysholm score between the 2 groups during the observation period was detected

51 patients (25 vs. 26) + Darabos N, 201125 Randomized trial (ACS vs. Control) –

ACL recon.: hamstring (30) or patellar tendon (32)—BioTransFix (Arthrex) or RigidFix (Mytek) and interference screw

ACS was produced drawing venous blood into syringes containing pretreated glass beads, and after a period of incubation serum is extracted through centrifugation. Injection regime of 4 injections on Day 0 (day of surgery), Day 1, Day 6, and Day 10

Bone tunnel enlargement (by CT) was significantly less (6 months: 8%, 12 months: 13%) in ACS group than in control group (6 months: 31%, 12 months: 38%)

62 patients (31 vs. 31) - Vadala A, 201326 Randomized trial (PRP vs. Control) 40 patients (20 vs. 20) − Mirzatolooei F, 201327 Randomized trial (PRP vs. Control) –

ACL recon.: single-bundle quadrupled autograft of hamstrings—cross-pin and a bio-absorbable interference screw

Graft soaked in PRP solution (produced with double syringe system, Arthrex)

46 patients (23 vs. 23) − Silva A, 201028 Randomized trial (four groups) –

ACL recon.: hamstring tendons (double-bundle)—2 Endobutton for the AMT and PLT and 2 bioabsorbable interference screw in the tibia

PRP (produced with GPS III Kit, Biomet) and placed between the strands of the graft in each femoral tunnel

At 3-month post-op, all tunnels had enlarged compared to the diameter of the drill and most tunnels enlarged more in the midsection than at the aperture in a fusiform manner

The use of growth factors during and after surgery did not show any influence in the tunnel enlargement (p = .563)

40 patients (10 control vs. 10 PRP in FT vs. 10 PRP in FT and intra-articular at 2 and 4 weeks vs. 10 PRP activated with thrombin in FT) − Orrego M, 200829 Randomized trial (four groups) –

ACL recon.: quadruple semitendinosus-gracilis graft— biodegradable transfixing pin and biodegradable interference screw; BP placed by interference fit at the femoral tunnel.

5 mL PRP (produced with Biomet GPS II kit, Biomet) injected between the graft strands before passing it into the tunnel

The use of PC did not show any significant effect in the tunnel widening evolution at 6 months f-up

The use of a BP effectively prevented tunnel widening

The BP and PC combination did not show a synergic effect as compared to PC or BP individually

108 patients (27 control vs. 26 PC vs. 28 BP vs. 27 PC + BP) - Sözkesen S, 201830 Comparative study ACL recon.: hamstring autograft without PRP. PRP administration into the femoral and tibial tunnel –

The patients were evaluated preoperatively and postoperatively with the IKDC score, Lysholm score, Tegner activity scale and a KT-1000 arthrometer device

No difference was seen between clinical examination results and the grading scales used

ACL graft-bone interface/integration + Rupreht M, 201331 Randomized trial (PRP vs. Control) –

ACL recon.: double-looped semitendinosus and gracilis tendon autograft—bioabsorbable cross pins and bioabsorbable interference screw

PRP was applied after autograft positioning, into the femoral and tibial tunnels (1 ml in each of them), and onto the graft itself (3 ml)

41 patients (21 vs. 20) + Vogrin M, 201032 Randomized trial (PRP vs. Control) –

ACL recon.: double-looped semitendinosus and gracilis tendon graft—bioabsorbable cross pins and bioabsorbable interference screw

PRP produced with Magellan system (Medtronic) and applied into the femoral and tibial tunnels as well as onto the graft itself

After 4–6 weeks, significantly higher level of vascularization in the osteoligamentous interface in PRP group (0.33 ± 0.09 vs. 0.16 ± 0.09, p < .001)

In the intra-articular part of the graft, no evidence of revascularization in either group

41 patients (21 vs. 20) - Del Torto M, 201520 Prospective comparative study (PRFM vs. Control) –

MRI evaluation considering graft–tunnel interface and graft signal intensity provided similar results between the two examined groups, without any statistically significant difference. In the majority of the cases, a good signal quality of the graft and a scarce film of synovial fluid at the graft–tunnel interface were observed

28 patients (14 vs. 14) − Silva A, 201415 Randomized trial (BMC vs. Control) –

ACL recon.: double-looped semitendinosus and gracilis tendon autograft—Toggleloc Ziploop (Biomet) and bioabsorbable interference screw (Biomet)

Bone marrow harvested from the iliac crest and concentrate to obtain 3 ml BMC. 1.5 ml injected inside the femoral end of the graft itself before graft positioning; the remaining 1.5 ml BMC injected within the tunnel around the graft, from the bottom down to the entrance of the tunnel

43 patients (20 vs. 23) − Azcarate AV, 201434 Randomized trial (PRP vs. PRGF vs. Control) –

ACL recon: patellar tendon allograft transtibial technique—RigidFix (DePuy Mitek) and biodegradable (Byocril) interference screw

PRP produced with a double-spin procedure using a standard centrifuge

PRP produced following Anitua's technique (PRGF-Endoret® Technology)

No statistically significant differences between groups in intensity, thickness, and uniformity of grafts at 6 months MRI

150 patients (50 vs. 50 vs. 50) − Figueroa D, 201035 Comparative study (PRP vs. Control) 50 patients (30 vs. 20) − Silva A, 200936 Randomized trial (four groups) –

ACL recon.: Double-bundle autologous hamstring tendons—Endobutton for the AMT and PLT and 2 bioabsorbable interference screws

PRP (produced with Mini GPS III Kit, Biomet) and placed between the strands of the graft in each femoral tunnel

40 patients (10 control vs. 10 PRP in FT vs. 10 PRP in FT and intra-articular at 2- and 4 weeks vs. 10 PRP activated with thrombin in FT) Orrego M, 200829 Randomized trial (four groups) –

ACL recons.: quadruple semitendinosus-gracilis graft—biodegradable transfixing pin and biodegradable interference screw

BP placed by interference fit at the femoral tunnel

5 ml PRP (produced with GPS II kit, Biomet) added between the graft strands before passing it into the tunnel. After fixation, 1 ml of PRP injected into the femoral tunnel between the graft strands

108 patients (27 control vs. 26 PC vs. 28 BP vs. 27 PC + BP) - Beyzadeoglu T, 202019 Cohort study (PRF vs. control) ACL recon.: semitendinosus tendon graft with growth factors and activated platelets –

PRF-treated grafts demonstrated lower MRI signal intensity and less fluid in the graft-tunnel interface as compared with controls

No clinical benefit of PRF could be demonstrated in clinical outcomes

44 patients (23 vs. 21) Application of PRF led to superior graft integration and maturation in the proximal third of the ACL graft ACL graft remodeling + Seijas R, 201337 Randomized trial (PRP vs. Control) –

ACL recon.: patellar tendon graft with 9 mm bone plugs—hydroxyapatite screws in femur and tibia.

8 ml of PRP produced with PRGF technique (BTI Systems Vitoria, Spain)

More patients in the PRP group than controls attained higher stages of remodeling at month 4 (p = .003), month 6 (p = .0001), and month 12 (but NS p = .354)

98 patients (49 vs. 49) Rupreht M, 201338 Randomized trial (PRP vs. Control) –

ACL recon.: double-looped semitendinosus and gracilis tendon autograft—bioabsorbable cross pins in and bioabsorbable interference screw

PRP was applied after autograft positioning, into the femoral and tibial tunnels (1 ml in each of them), and onto the graft itself (3 ml)

41 patients (21 vs. 20) Radice F, 201039 Comparative study (PRP vs. Control) –

ACL recon.: BPTB autograft (15 vs. 10) or Harmstring (10 vs. 15). Fixation in BPTB autograft with metallic interference screws, in hamstring autograft with metallic or bioabsorbable cross-pin/bioabsorbable screw with a metallic staple in the proximal tibia

PRP (produced with GPS III Kit, Biomet)

ACL reconstruction with the use of PRPG achieves complete homogeneous grafts assessed by MRI, in 179 days compared with 369 days for ACL reconstruction without PRPG. This represents a time shortening of 48% with respect to ACL reconstruction without PRPG

50 patients (25 vs. 25) Sanchez M, 201040 Comparative study (PRP vs. Control) –

ACL recon.: hamstring tendons—transcondylar screw proximally and PRGF-treated bone plug and 2 metal staples distally.

6 ml PRP produced with BTI System II (BTI Biotechnology Institute)

PRGF resulted in more mature tissue than controls at histology (p = .024)

Histologically evident newly formed connective tissue enveloping the graft present in 77.3% of PRGF-treated grafts and 40% of controls

Overall, arthroscopic evaluations were not statistically different between PRGF and control groups (p = .051)

37 patients (22 vs. 15) Orrego M, 200829 Randomized trial (four groups) –

ACL recon.: quadruple semitendinosus-gracilis graft— biodegradable transfixing pin and biodegradable inter-ference screw; BP placed by interference fit at the femoral tunnel

5 ml PRP (produced with Biomet GPS II kit, Biomet) added between the graft strands before passing it into the tunnel

108 patients (27 control vs. 26 PC vs. 28 BP vs. 27 PC + BP) Ventura A, 200541 Randomized trial (PRP vs. Control)

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