Shoulder:Rotator Cuff Pathology/Biology of Rotator Cuff Healing - Revision history

Alexandre.laedermann at 11:56, 7 June 2021

2021-06-07T11:56:01Z

Alexandre.laedermann at 11:46, 7 June 2021

2021-06-07T11:46:35Z

Show changes

Alexandre.laedermann at 10:56, 7 June 2021

2021-06-07T10:56:40Z

Show changes

Alexandre.laedermann at 10:38, 7 June 2021

2021-06-07T10:38:15Z

Alexandre.laedermann at 10:19, 7 June 2021

2021-06-07T10:19:37Z

Alexandre.laedermann at 09:51, 7 June 2021

2021-06-07T09:51:59Z

Alexandre.laedermann at 09:39, 7 June 2021

2021-06-07T09:39:38Z

Alexandre.laedermann at 09:27, 7 June 2021

2021-06-07T09:27:36Z

Alexandre.laedermann at 08:59, 7 June 2021

2021-06-07T08:59:18Z

Show changes

Alexandre.laedermann: /* Drugs that may Augment Rotator Cuff Muscle */

2020-01-07T19:15:53Z

Drugs that may Augment Rotator Cuff Muscle

@@ Line 197: / Line 197: @@
 ====Using Xenografts to Augment the Enthesis====
-Extracellular matrix patches are scaffold devices designed to create a cellular reaction that leads to an inflammatory response, host cell infiltration, and tendon-like remodeling. Even though the augmentation using porcine small intestine submucosa has shown to improve the histological healing properties (e.g. tendon-like remodeling) in several animal studies, clinical studies, where large to massive chronic rotator cuff tears were augmented using a similar scaffold showed no differences in the clinical outcome when compared to a control group.<ref>Nicholson GP, Breur GJ, Van Sickle D, Yao JQ, Kim J, Blanchard CR. Evaluation of a cross-linked acellular porcine dermal patch for rotator cuff repair augmentation in an ovine model. J Shoulder Elbow Surg. 2007;16(5 Suppl):S184-90.</ref><ref>Iannotti JP, Codsi MJ, Kwon YW, Derwin K, Ciccone J, Brems JJ. Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88(6):1238-44.</ref>
+Extracellular matrix patches are scaffold devices designed to create a cellular reaction that leads to an inflammatory response, host cell infiltration, and tendon-like remodeling. Even though the augmentation using porcine small intestine submucosa has shown to improve the histological healing properties (e.g. tendon-like remodeling) in several animal studies, clinical studies, where large to massive chronic rotator cuff tears were augmented using a similar scaffold showed no differences in the clinical outcome when compared to a control group.<ref>Nicholson GP, Breur GJ, Van Sickle D, Yao JQ, Kim J, Blanchard CR. Evaluation of a cross-linked acellular porcine dermal patch for rotator cuff repair augmentation in an ovine model. J Shoulder Elbow Surg. 2007;16(5 Suppl):S184-90.</ref><ref>Iannotti JP, Codsi MJ, Kwon YW, Derwin K, Ciccone J, Brems JJ. Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88:1238-44.</ref>
-Another group reported that 4 out of 19 (21%) patients treated with the same xenograft had a severe postoperative inflammatory reaction, which made a reoperation with a debridement and removal of the graft necessary. Since all the intraoperative cultures were negative, this reaction was most likely caused by the xenograft itself. Furthermore, no clinical benefit could be shown after a 2 year follow-up.<ref>Walton JR, Bowman NK, Khatib Y, Linklater J, Murrell GA. Restore orthobiologic implant: not recommended for augmentation of rotator cuff repairs. J Bone Joint Surg Am. 2007;89(4):786-91.</ref>
+Another group reported that 4 out of 19 (21%) patients treated with the same xenograft had a severe postoperative inflammatory reaction, which made a reoperation with a debridement and removal of the graft necessary. Since all the intraoperative cultures were negative, this reaction was most likely caused by the xenograft itself. Furthermore, no clinical benefit could be shown after a 2 year follow-up.<ref>Walton JR, Bowman NK, Khatib Y, Linklater J, Murrell GA. Restore orthobiologic implant: not recommended for augmentation of rotator cuff repairs. J Bone Joint Surg Am. 2007;89:786-91.</ref>
-Inconsistent results were reported when using Permacol, an acellular porcine dermal collagen matrix. It is cross-linked and thus not susceptible to enzymatic degradation. Badhe et al. reported good results 4.5 years after augmenting massive tears in 10 patients with an intact repair in eight, and a retear in only two patients. On the other hand, Soler et al. were using Permacol as a bridging device. All of the four reconstructions failed within six months postoperatively and had signs of inflammation. No differences were seen when using extracellular matrix scaffolds in open revision surgery.<ref>Badhe SP, Lawrence TM, Smith FD, Lunn PG. An assessment of porcine dermal xenograft as an augmentation graft in the treatment of extensive rotator cuff tears. J Shoulder Elbow Surg. 2008;17(1 Suppl):35S-9S.</ref><ref>Sears BW, Choo A, Yu A, Greis A, Lazarus M. Clinical outcomes in patients undergoing revision rotator cuff repair with extracellular matrix augmentation. Orthopedics. 2015;38(4):e292-6.</ref><ref>Soler JA, Gidwani S, Curtis MJ. Early complications from the use of porcine dermal collagen implants (Permacol) as bridging constructs in the repair of massive rotator cuff tears. A report of 4 cases. Acta Orthop Belg. 2007;73(4):432-6.</ref>
+Inconsistent results were reported when using Permacol, an acellular porcine dermal collagen matrix. It is cross-linked and thus not susceptible to enzymatic degradation. Badhe et al. reported good results 4.5 years after augmenting massive tears in 10 patients with an intact repair in eight, and a retear in only two patients. On the other hand, Soler et al. were using Permacol as a bridging device. All of the four reconstructions failed within six months postoperatively and had signs of inflammation. No differences were seen when using extracellular matrix scaffolds in open revision surgery.<ref>Badhe SP, Lawrence TM, Smith FD, Lunn PG. An assessment of porcine dermal xenograft as an augmentation graft in the treatment of extensive rotator cuff tears. J Shoulder Elbow Surg. 2008;17(1 Suppl):35S-9S.</ref><ref>Sears BW, Choo A, Yu A, Greis A, Lazarus M. Clinical outcomes in patients undergoing revision rotator cuff repair with extracellular matrix augmentation. Orthopedics. 2015;38:e292-6.</ref><ref>Soler JA, Gidwani S, Curtis MJ. Early complications from the use of porcine dermal collagen implants (Permacol) as bridging constructs in the repair of massive rotator cuff tears. A report of 4 cases. Acta Orthop Belg. 2007;73:432-6.</ref>
-More promising results were reported in a study of 9 patients with massive, otherwise unrepairable rotator cuff tears, that have received a porcine dermal collagen patch augmentation. After a minimum follow-up of 2.5 years, all cases showed complete functional recovery as well as covering of the humeral head. Another prospective comparative study showed a reduction of the retear rate and improved clinical outcome scores after ECM augmentation of arthroscopic repairs of large to massive tears.<ref>Gilot GJ, Alvarez-Pinzon AM, Barcksdale L, Westerdahl D, Krill M, Peck E. Outcome of Large to Massive Rotator Cuff Tears Repaired With and Without Extracellular Matrix Augmentation: A Prospective Comparative Study. Arthroscopy. 2015;31(8):1459-65.</ref><ref>Giannotti S, Ghilardi M, Dell'osso G, Magistrelli L, Bugelli G, Di Rollo F, et al. Study of the porcine dermal collagen repair patch in morpho-functional recovery of the rotator cuff after minimum follow-up of 2.5 years. Surgical technology international. 2014;24:348-52.</ref>
+More promising results were reported in a study of 9 patients with massive, otherwise unrepairable rotator cuff tears, that have received a porcine dermal collagen patch augmentation. After a minimum follow-up of 2.5 years, all cases showed complete functional recovery as well as covering of the humeral head. Another prospective comparative study showed a reduction of the retear rate and improved clinical outcome scores after ECM augmentation of arthroscopic repairs of large to massive tears.<ref>Gilot GJ, Alvarez-Pinzon AM, Barcksdale L, Westerdahl D, Krill M, Peck E. Outcome of Large to Massive Rotator Cuff Tears Repaired With and Without Extracellular Matrix Augmentation: A Prospective Comparative Study. Arthroscopy. 2015;31:1459-65.</ref><ref>Giannotti S, Ghilardi M, Dell'osso G, Magistrelli L, Bugelli G, Di Rollo F, Ricci G, Calabrese R, Siciliano G, Guido G. Study of the porcine dermal collagen repair patch in morpho-functional recovery of the rotator cuff after minimum follow-up of 2.5 years. Surgical technology international. 2014;24:348-52.</ref>
 ====Using Allografts to Augment the Enthesis====
-When using GraftJacket allograft acellular human dermal matrix for the augmentation of large to massive tears, good results were reported. In a prospective, randomized study, an arthroscopic reconstruction of tears larger than 3 cm was performed with either a GraftJacket augmentation (n= 20) or without augmentation (n= 22). After a follow up of 12 to 24 months (mean 14.5 months), significantly more intact repairs were found in the GraftJacket group (85%) compared to the control group (40%). American Shoulder and Elbow Surgeons and Constant scores in the GraftJacket group were statistically better at last follow-up.<ref>Barber FA, Burns JP, Deutsch A, Labbe MR, Litchfield RB. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. 2012;28(1):8-15.</ref><ref>Wong I, Burns J, Snyder S. Arthroscopic GraftJacket repair of rotator cuff tears. J Shoulder Elbow Surg. 2010;19(2 Suppl):104-9.</ref>
+When using GraftJacket allograft acellular human dermal matrix for the augmentation of large to massive tears, good results were reported. In a prospective, randomized study, an arthroscopic reconstruction of tears larger than 3 cm was performed with either a GraftJacket augmentation (n= 20) or without augmentation (n= 22). After a follow up of 12 to 24 months (mean 14.5 months), significantly more intact repairs were found in the GraftJacket group (85%) compared to the control group (40%). American Shoulder and Elbow Surgeons and Constant scores in the GraftJacket group were statistically better at last follow-up.<ref>Barber FA, Burns JP, Deutsch A, Labbe MR, Litchfield RB. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. 2012;28:8-15.</ref><ref>Wong I, Burns J, Snyder S. Arthroscopic GraftJacket repair of rotator cuff tears. J Shoulder Elbow Surg. 2010;19(2 Suppl):104-9.</ref>
 ====Using Synthetic Scaffolds to Augment the Enthesis====
-Synthetic patch augmentation has shown to protect the repair site and reduce friction in the subacromial space. Ciampi et al. were able to show, in a cohort of 152 patients with posterosuperior tears, a significant decrease in retear rate of 17% in the polypropylene patch augmentation group compared to 51% in the repair-only group at 1-year follow-up, as well as increased abduction strength and elevation at 3-year follow-up.<ref>Ciampi P, Scotti C, Nonis A, Vitali M, Di Serio C, Peretti GM, et al. The benefit of synthetic versus biological patch augmentation in the repair of posterosuperior massive rotator cuff tears: a 3-year follow-up study. Am J Sports Med. 2014;42(5):1169-75.</ref>
+Synthetic patch augmentation has shown to protect the repair site and reduce friction in the subacromial space. Ciampi et al. were able to show, in a cohort of 152 patients with posterosuperior tears, a significant decrease in retear rate of 17% in the polypropylene patch augmentation group compared to 51% in the repair-only group at 1-year follow-up, as well as increased abduction strength and elevation at 3-year follow-up.<ref>Ciampi P, Scotti C, Nonis A, Vitali M, Di Serio C, Peretti GM, Fraschini G. The benefit of synthetic versus biological patch augmentation in the repair of posterosuperior massive rotator cuff tears: a 3-year follow-up study. Am J Sports Med. 2014;42:1169-75.</ref>
-Poly-l-lactic acid bioabsorbable patches designed specifically to reinforce the surgical repair of tendons supported successful repair of large to massive tears in 83% of patients at 12 months after surgery and 78% of patients at 42 months after surgery, with substantial functional improvement.<ref>Proctor CS. Long-term successful arthroscopic repair of large and massive rotator cuff tears with a functional and degradable reinforcement device. J Shoulder Elbow Surg. 2014;23(10):1508-13.</ref>
+Poly-l-lactic acid bioabsorbable patches designed specifically to reinforce the surgical repair of tendons supported successful repair of large to massive tears in 83% of patients at 12 months after surgery and 78% of patients at 42 months after surgery, with substantial functional improvement.<ref>Proctor CS. Long-term successful arthroscopic repair of large and massive rotator cuff tears with a functional and degradable reinforcement device. J Shoulder Elbow Surg. 2014;23:1508-13.</ref>
 Promising results were also reported when using a bi-layered, absorbable reinforced poly (4)-hydroxybutyrate scaffold that can be used to reinforce rotator cuff reconstruction. Augmenting the tear using this scaffold lead to improved repair integrity of 96% in 50 patients at the 6 month follow-up with no additional failure at the 1 year follow-up.<ref>Barbash S, Denny C, Collin P, Reish T, Hart JM, Brockmeier SF. Clinical Outcomes and Structural Healing After Arthroscopic Rotator Cuff Repair Reinforced With A Novel Absorbable Biologic Scaffold: A Prospective, Multicenter Trial. Orthopaedic Journal of Sports Medicine. 2015;3(2 suppl).</ref>
-Another interesting approach is the combination of a synthetic patch with an autologous long head of the biceps tendon interposition in irreparable tears. A study in 60 patients showed a retear rate at 12 months follow-up of 15% compared to 40% in the control group. It is unclear though, if the synthetic patch, the long head of the biceps tendon or the combination of the two lead to the improved retear rate.<ref>Vitali M, Cusumano A, Pedretti A, Naim Rodriguez N, Fraschini G. Employment of synthetic patch with augmentation of the long head of the biceps tendon in irreparable lesions of the rotator cuff: our technique applied to 60 patients. Tech Hand Up Extrem Surg. 2015;19(1):32-9.</ref>
+Another interesting approach is the combination of a synthetic patch with an autologous long head of the biceps tendon interposition in irreparable tears. A study in 60 patients showed a retear rate at 12 months follow-up of 15% compared to 40% in the control group. It is unclear though, if the synthetic patch, the long head of the biceps tendon or the combination of the two lead to the improved retear rate.<ref>Vitali M, Cusumano A, Pedretti A, Naim Rodriguez N, Fraschini G. Employment of synthetic patch with augmentation of the long head of the biceps tendon in irreparable lesions of the rotator cuff: our technique applied to 60 patients. Tech Hand Up Extrem Surg. 2015;19:32-9.</ref>
 ==Augmentation of the Rotator Cuff Muscle==
@@ Line 221: / Line 221: @@
 ===Platelet Concentrates to Augment the Rotator Cuff Muscle===
-There is evidence in the literature that the application of platelet concentrates may have a positive effect on muscle healing, improved pain relief, as well as a quicker return to sport. Others reported no differences with respect to time to return to sport or re-injury rate 1 year after injecting a platelet concentrate into the hamstrings after acute hamstring injuries. In all the above studies, acute muscle injuries were treated with platelet concentrate injections. As the mechanism of muscle-injury after tendon tear is different from an acute muscle injury, it is questionable to what extent these results can be transferred to a chronic rotator cuff tear muscle model. Whether platelet rich concentrates improve muscle quality after rotator cuff tear is unclear and not reported in the literature.<ref>Wright-Carpenter T, Klein P, Schaferhoff P, Appell HJ, Mir LM, Wehling P. Treatment of muscle injuries by local administration of autologous conditioned serum: a pilot study on sportsmen with muscle strains. Int J Sports Med. 2004;25(8):588-93.</ref><ref>Bubnov R, Yevseenko V, Semeniv I. Ultrasound guided injections of platelets rich plasma for muscle injury in professional athletes. Comparative study. Medical ultrasonography. 2013;15(2):101-5.</ref>
+There is evidence in the literature that the application of platelet concentrates may have a positive effect on muscle healing, improved pain relief, as well as a quicker return to sport. Others reported no differences with respect to time to return to sport or re-injury rate 1 year after injecting a platelet concentrate into the hamstrings after acute hamstring injuries. In all the above studies, acute muscle injuries were treated with platelet concentrate injections. As the mechanism of muscle-injury after tendon tear is different from an acute muscle injury, it is questionable to what extent these results can be transferred to a chronic rotator cuff tear muscle model. Whether platelet rich concentrates improve muscle quality after rotator cuff tear is unclear and not reported in the literature.<ref>Wright-Carpenter T, Klein P, Schaferhoff P, Appell HJ, Mir LM, Wehling P. Treatment of muscle injuries by local administration of autologous conditioned serum: a pilot study on sportsmen with muscle strains. Int J Sports Med. 2004;25:588-93.</ref><ref>Bubnov R, Yevseenko V, Semeniv I. Ultrasound guided injections of platelets rich plasma for muscle injury in professional athletes. Comparative study. Medical ultrasonography. 2013;15:101-5.</ref>
 ===Cells to Augment the Rotator Cuff Muscle===
@@ Line 229: / Line 229: @@
 Poly (ADP-ribose) 4 polymerase-1 (PARP-1) has been shown to be a key regulator of inflammation, apoptosis, muscle atrophy, muscle regeneration as well as adipodyte development. In PARP-1 knock-out (PARP-1 KO) mice, a team performed a combined tenotomy of the supra- and infraspinatus muscle and found significant less muscle retraction (p=0.008) and less fatty infiltration (p=0.028) after 12 weeks and a significant decrease in the expression of inflammatory, apoptotic, adipogenic and muscular atrophy genes at both the 1 week and 6 week time points in the PARP-1 KO group compared to the WT group. The PARP-1 KO group also showed a significant decrease in the expression of inflammatory, apoptotic, adipogenic and muscular atrophy genes at both the 1 week and 6 weeks time points. Therefore, PARP-1 is not only a key regulator of muscular deterioration, but may also be an interesting target to improve muscular properties after rotator cuff tear and repair using a PARP-1 inhibitor.<ref name=":0" />
-The application of nandrolone decanoate, an anabolic steroid has shown to not only prevent muscle atrophy but also fatty infiltration in animal models making this drug an interesting treatment option for the prevention of muscle degeneration after tear.<ref>Gerber C, Meyer DC, Fluck M, Benn MC, von Rechenberg B, Wieser K. Anabolic Steroids Reduce Muscle Degeneration Associated With Rotator Cuff Tendon Release in Sheep. Am J Sports Med. 2015;43(10):2393-400.</ref>
+The application of nandrolone decanoate, an anabolic steroid has shown to not only prevent muscle atrophy but also fatty infiltration in animal models making this drug an interesting treatment option for the prevention of muscle degeneration after tear.<ref>Gerber C, Meyer DC, Fluck M, Benn MC, von Rechenberg B, Wieser K. Anabolic Steroids Reduce Muscle Degeneration Associated With Rotator Cuff Tendon Release in Sheep. Am J Sports Med. 2015;43:2393-400.</ref>
-It has been proposed that vitamin D blood levels negatively correlate with fatty infiltration after tear and positively correlate with muscle torque in the same patients.<ref>Oh JH, Kim SH, Kim JH, Shin YH, Yoon JP, Oh CH. The level of vitamin D in the serum correlates with fatty degeneration of the muscles of the rotator cuff. J Bone Joint Surg Br. 2009;91(12):1587-93.</ref>
+It has been proposed that vitamin D blood levels negatively correlate with fatty infiltration after tear and positively correlate with muscle torque in the same patients.<ref>Oh JH, Kim SH, Kim JH, Shin YH, Yoon JP, Oh CH. The level of vitamin D in the serum correlates with fatty degeneration of the muscles of the rotator cuff. J Bone Joint Surg Br. 2009;91:1587-93.</ref>
 This suggests that a Vitamin D substitution would have a positive impact on muscular changes after tears and repairs. However, in a clinical study, there was no correlation between rotator cuff healing and vitamin D blood levels.<ref name=":1" />

@@ Line 205: / Line 205: @@
 More promising results were reported in a study of 9 patients with massive, otherwise unrepairable rotator cuff tears, that have received a porcine dermal collagen patch augmentation. After a minimum follow-up of 2.5 years, all cases showed complete functional recovery as well as covering of the humeral head. Another prospective comparative study showed a reduction of the retear rate and improved clinical outcome scores after ECM augmentation of arthroscopic repairs of large to massive tears.<ref>Gilot GJ, Alvarez-Pinzon AM, Barcksdale L, Westerdahl D, Krill M, Peck E. Outcome of Large to Massive Rotator Cuff Tears Repaired With and Without Extracellular Matrix Augmentation: A Prospective Comparative Study. Arthroscopy. 2015;31(8):1459-65.</ref><ref>Giannotti S, Ghilardi M, Dell'osso G, Magistrelli L, Bugelli G, Di Rollo F, et al. Study of the porcine dermal collagen repair patch in morpho-functional recovery of the rotator cuff after minimum follow-up of 2.5 years. Surgical technology international. 2014;24:348-52.</ref>
-==== Using Allografts to Augment the Enthesis ====
+====Using Allografts to Augment the Enthesis====
 When using GraftJacket allograft acellular human dermal matrix for the augmentation of large to massive tears, good results were reported. In a prospective, randomized study, an arthroscopic reconstruction of tears larger than 3 cm was performed with either a GraftJacket augmentation (n= 20) or without augmentation (n= 22). After a follow up of 12 to 24 months (mean 14.5 months), significantly more intact repairs were found in the GraftJacket group (85%) compared to the control group (40%). American Shoulder and Elbow Surgeons and Constant scores in the GraftJacket group were statistically better at last follow-up.<ref>Barber FA, Burns JP, Deutsch A, Labbe MR, Litchfield RB. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. 2012;28(1):8-15.</ref><ref>Wong I, Burns J, Snyder S. Arthroscopic GraftJacket repair of rotator cuff tears. J Shoulder Elbow Surg. 2010;19(2 Suppl):104-9.</ref>
-==== Using Synthetic Scaffolds to Augment the Enthesis ====
+====Using Synthetic Scaffolds to Augment the Enthesis====
 Synthetic patch augmentation has shown to protect the repair site and reduce friction in the subacromial space. Ciampi et al. were able to show, in a cohort of 152 patients with posterosuperior tears, a significant decrease in retear rate of 17% in the polypropylene patch augmentation group compared to 51% in the repair-only group at 1-year follow-up, as well as increased abduction strength and elevation at 3-year follow-up.<ref>Ciampi P, Scotti C, Nonis A, Vitali M, Di Serio C, Peretti GM, et al. The benefit of synthetic versus biological patch augmentation in the repair of posterosuperior massive rotator cuff tears: a 3-year follow-up study. Am J Sports Med. 2014;42(5):1169-75.</ref>
@@ Line 233: / Line 233: @@
 It has been proposed that vitamin D blood levels negatively correlate with fatty infiltration after tear and positively correlate with muscle torque in the same patients.<ref>Oh JH, Kim SH, Kim JH, Shin YH, Yoon JP, Oh CH. The level of vitamin D in the serum correlates with fatty degeneration of the muscles of the rotator cuff. J Bone Joint Surg Br. 2009;91(12):1587-93.</ref>
-This suggests that a Vitamin D substitution would have a positive impact on muscular changes after tears and repairs. However in a clinical study, there was no correlation between rotator cuff healing and vitamin D blood levels.<ref>Ryu KJ, Kim BH, Lee Y, Dan J, Kim JH. Low Serum Vitamin D Is Not Correlated With the Severity of a Rotator Cuff Tear or Retear After Arthroscopic Repair. Am J Sports Med. 2015;43(7):1743-50.
+This suggests that a Vitamin D substitution would have a positive impact on muscular changes after tears and repairs. However, in a clinical study, there was no correlation between rotator cuff healing and vitamin D blood levels.<ref>Ryu KJ, Kim BH, Lee Y, Dan J, Kim JH. Low Serum Vitamin D Is Not Correlated With the Severity of a Rotator Cuff Tear or Retear After Arthroscopic Repair. Am J Sports Med. 2015;43(7):1743-50.
 </ref>
 ==Conclusion==
-Due to the high retear rate after reconstruction, there is a great interest in it’s biological augmentation. Even though cytokines have shown the potential to improve the healing in animal models, there is little information about the correct concentration and timing of the more than 1500 cytokines that interact during the healing process. Further studies are necessary to identify the right combination, timing and concentration of the cytokines. Tendinopathies and partial-thickness tears may be interesting targets for the biological augmentation of the rotator cuff. Yet we must be aware that animal studies have shown that, instead of a physiological enthesis, an abundance of scar tissue is formed. Using stem cells to biologically augment the reconstruction might have a great potential since these cells can be differentiated into different cell types that are important for the healing process. However, further studies are necessary to understand how to control these stem cells in a safe and efficient way. Finally, much basic research is required to overcome the problems associated with using grafts as well as developing new drugs for the augmentation of rotator cuff reconstruction.
+Due to the high retear rate of the rotator cuff muscle after reconstruction, there is a great interest in its biological augmentation. Even though cytokines have shown the potential to improve the healing in animal models, there is little information about the correct concentration and timing of the more than 1500 cytokines that interact during the healing process. Further studies are necessary to identify the right combination, timing and concentration of the cytokines. Tendinopathies and partial-thickness tears may be interesting targets for the biological augmentation of the rotator cuff. Yet we must be aware that animal studies have shown that, instead of a physiological enthesis, an abundance of scar tissue is formed. Using stem cells to biologically augment the reconstruction might have a great potential since these cells can be differentiated into different cell types that are important for the healing process. However, further studies are necessary to understand how to control these stem cells in a safe and efficient way. Finally, more basic research is required to overcome the problems associated with using grafts as well as developing new drugs for the augmentation of rotator cuff reconstruction.
 <references />

@@ Line 157: / Line 157: @@
 There is evidence that mesenchymal stem cells may improve rotator cuff repair healing. The possibility to harvest bone marrow aspirate concentrate during reconstruction in a more or less standardized manner and the fact that bone marrow aspirate concentrate apart from other cells and platelets, contains mesenchymal stem cells has made bone marrow aspirate concentrate a promising option for a biological augmentation of the repair.
-There is limited literature investigating the clinical effect of the biological augmentation using mesenchymal stem cells or bone marrow aspirate concentrate to improve healing. In a study published in 2014, Hernigou et al. showed that arthroscopic reconstructions that were augmented with bone marrow derived mesenchymal stem cells showed a 13% retear rate 10 years postoperatively compared to 46% in the control group, that only received a rotator cuff single row repair without application of mesenchymal stem cells<ref>Hernigou P, Flouzat Lachaniette CH, Delambre J, Zilber S, Duffiet P, Chevallier N, et al. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop. 2014;38(9):1811-8.</ref>
+There is limited literature investigating the clinical effect of the biological augmentation using mesenchymal stem cells or bone marrow aspirate concentrate to improve healing. In a study published in 2014, Hernigou et al. showed that arthroscopic reconstructions that were augmented with bone marrow derived mesenchymal stem cells showed a 13% retear rate 10 years postoperatively compared to 46% in the control group, that only received a rotator cuff single row repair without application of mesenchymal stem cells.<ref>Hernigou P, Flouzat Lachaniette CH, Delambre J, Zilber S, Duffiet P, Chevallier N, et al. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop. 2014;38(9):1811-8.</ref>
-In another study 14 patients with complete rotator cuff tears received a reconstruction with a subsequent injection of autologous bone marrow derived stem cells. The MRI analysis, that was performed 12 months after surgery revealed good tendon integrity in all the subjects. Clinical findings remained unaltered in the following year in all but one patient, who relapsed into loss of strength and pain, considered a bad result. However, a limitation of this study was the absence of a control group and the rather small study population.<ref>Ellera Gomes JL, da Silva RC, Silla LM, Abreu MR, Pellanda R. Conventional rotator cuff repair complemented by the aid of mononuclear. Knee Surg Sports Traumatol Arthrosc. 2012;20(2):373-7.</ref>
+In another study 14 patients with complete rotator cuff tears received a reconstruction with a subsequent injection of autologous bone marrow derived stem cells. The MRI analysis, that was performed 12 months after surgery revealed good tendon integrity in all the subjects. Clinical findings remained unaltered in the following year in all but one patient, who relapsed into loss of strength and pain, considered as a bad result. However, a limitation of this study was the absence of a control group and the rather small study population.<ref>Ellera Gomes JL, da Silva RC, Silla LM, Abreu MR, Pellanda R. Conventional rotator cuff repair complemented by the aid of mononuclear. Knee Surg Sports Traumatol Arthrosc. 2012;20(2):373-7.</ref>
 Several studies have investigated the isolation and characterization of mesenchymal stem cells harvested from different shoulder tissues. Mazzocca et al. were able to harvest mesenchymal stem cells from the bone marrow through the anchor tunnel of the humeral head during arthroscopic reconstructions. These cells were then cultivated. Doing so, the authors were able to produce connective tissue progenitor cells, which have the potential of being used in future operations.<ref>Mazzocca AD, McCarthy MB, Chowaniec DM, Cote MP, Arciero RA, Drissi H. Rapid isolation of human stem cells (connective tissue progenitor cells) from the. Am J Sports Med. 2010;38(7):1438-47.</ref>
@@ Line 182: / Line 182: @@
 ===Scaffold based Augmentation===
-The application of scaffolds is another promising way of augmenting reconstruction sites, especially when dealing with large and complex rotator cuff tears. Even though a scaffold interposition may help bridging rotator cuff tendon defects, it does not address the issues related to rotator cuff retraction, namely the reduced irreversible biomechanical properties of the rotator cuff muscle. The use of interposition scaffolds in rotator cuff repair is therefore questionable. On the other hand, scaffolds with which the tendon is augmented not only may increase the initial strength of the reconstruction and allow gradual tissue ingrowth, but also protect the healing tissue. Three different types of scaffolds exist (Table);
+The application of scaffolds is another promising way of augmenting reconstruction sites, especially when dealing with large and complex rotator cuff tears. Even though a scaffold interposition may help bridging rotator cuff tendon defects, it does not address the issues related to rotator cuff retraction, namely the reduced irreversible biomechanical properties of the rotator cuff muscle. The use of interposition scaffolds in rotator cuff repair is therefore questionable. On the other hand, scaffolds with which the tendon is augmented not only may increase the initial strength of the reconstruction and allow gradual tissue ingrowth, but also protect the healing tissue. Three different types of scaffolds exist (Table 4):
 . Xenografts (graft transferred from another species)
@@ Line 190: / Line 190: @@
 . Synthetic Grafts
-'''''Scaffolds can be divided into three categories. This table shows the most popular commercially available scaffolds in each category.'''''
+'''''Table 4. Scaffolds can be divided into three categories. This table shows the most popular commercially available scaffolds in each category.'''''
 [[File:1562839288113-lg.jpg|none|thumb|600x600px]]
@@ Line 201: / Line 201: @@
 Another group reported that 4 out of 19 (21%) patients treated with the same xenograft had a severe postoperative inflammatory reaction, which made a reoperation with a debridement and removal of the graft necessary. Since all the intraoperative cultures were negative, this reaction was most likely caused by the xenograft itself. Furthermore, no clinical benefit could be shown after a 2 year follow-up.<ref>Walton JR, Bowman NK, Khatib Y, Linklater J, Murrell GA. Restore orthobiologic implant: not recommended for augmentation of rotator cuff repairs. J Bone Joint Surg Am. 2007;89(4):786-91.</ref>
-Inconsistent results were reported when using Permacol, an acellular porcine dermal collagen matrix. It is cross-linked and thus not susceptible to enzymatic degradation. Badhe et al. reported good results 4.5 years after augmenting massive tears in 10 patients with an intact repair in eight, and a retear in only two patients. On the other hand, Soler et al. were using Permacol as a bridging device. All of the four reconstructions failed within six months postoperatively and had signs of inflammation. No differences were seen when using extracellular matrix scaffolds in open revision surgery<ref>Badhe SP, Lawrence TM, Smith FD, Lunn PG. An assessment of porcine dermal xenograft as an augmentation graft in the treatment of extensive rotator cuff tears. J Shoulder Elbow Surg. 2008;17(1 Suppl):35S-9S.</ref><ref>Sears BW, Choo A, Yu A, Greis A, Lazarus M. Clinical outcomes in patients undergoing revision rotator cuff repair with extracellular matrix augmentation. Orthopedics. 2015;38(4):e292-6.</ref><ref>Soler JA, Gidwani S, Curtis MJ. Early complications from the use of porcine dermal collagen implants (Permacol) as bridging constructs in the repair of massive rotator cuff tears. A report of 4 cases. Acta Orthop Belg. 2007;73(4):432-6.</ref>
+Inconsistent results were reported when using Permacol, an acellular porcine dermal collagen matrix. It is cross-linked and thus not susceptible to enzymatic degradation. Badhe et al. reported good results 4.5 years after augmenting massive tears in 10 patients with an intact repair in eight, and a retear in only two patients. On the other hand, Soler et al. were using Permacol as a bridging device. All of the four reconstructions failed within six months postoperatively and had signs of inflammation. No differences were seen when using extracellular matrix scaffolds in open revision surgery.<ref>Badhe SP, Lawrence TM, Smith FD, Lunn PG. An assessment of porcine dermal xenograft as an augmentation graft in the treatment of extensive rotator cuff tears. J Shoulder Elbow Surg. 2008;17(1 Suppl):35S-9S.</ref><ref>Sears BW, Choo A, Yu A, Greis A, Lazarus M. Clinical outcomes in patients undergoing revision rotator cuff repair with extracellular matrix augmentation. Orthopedics. 2015;38(4):e292-6.</ref><ref>Soler JA, Gidwani S, Curtis MJ. Early complications from the use of porcine dermal collagen implants (Permacol) as bridging constructs in the repair of massive rotator cuff tears. A report of 4 cases. Acta Orthop Belg. 2007;73(4):432-6.</ref>
 More promising results were reported in a study of 9 patients with massive, otherwise unrepairable rotator cuff tears, that have received a porcine dermal collagen patch augmentation. After a minimum follow-up of 2.5 years, all cases showed complete functional recovery as well as covering of the humeral head. Another prospective comparative study showed a reduction of the retear rate and improved clinical outcome scores after ECM augmentation of arthroscopic repairs of large to massive tears.<ref>Gilot GJ, Alvarez-Pinzon AM, Barcksdale L, Westerdahl D, Krill M, Peck E. Outcome of Large to Massive Rotator Cuff Tears Repaired With and Without Extracellular Matrix Augmentation: A Prospective Comparative Study. Arthroscopy. 2015;31(8):1459-65.</ref><ref>Giannotti S, Ghilardi M, Dell'osso G, Magistrelli L, Bugelli G, Di Rollo F, et al. Study of the porcine dermal collagen repair patch in morpho-functional recovery of the rotator cuff after minimum follow-up of 2.5 years. Surgical technology international. 2014;24:348-52.</ref>
-Using Allografts to Augment the Enthesis
+==== Using Allografts to Augment the Enthesis ====
-When using GraftJacket allograft acellular human dermal matrix for the augmentation of large to massive tears, good results were reported. In a prospective, randomized study, an arthroscopic reconstruction of tears larger than 3 cm was performed with either a GraftJacket augmentation (n= 20) or without augmentation (n= 22) After a follow up of 12 to 24 months (mean 14.5 months), significantly more intact repairs were found in the GraftJacket group (85%) compared to the control group (40%). American Shoulder and Elbow Surgeons and Constant scores in the GraftJacket group were statistically better at last follow-up.<ref>Barber FA, Burns JP, Deutsch A, Labbe MR, Litchfield RB. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. 2012;28(1):8-15.</ref><ref>Wong I, Burns J, Snyder S. Arthroscopic GraftJacket repair of rotator cuff tears. J Shoulder Elbow Surg. 2010;19(2 Suppl):104-9.</ref>
+When using GraftJacket allograft acellular human dermal matrix for the augmentation of large to massive tears, good results were reported. In a prospective, randomized study, an arthroscopic reconstruction of tears larger than 3 cm was performed with either a GraftJacket augmentation (n= 20) or without augmentation (n= 22). After a follow up of 12 to 24 months (mean 14.5 months), significantly more intact repairs were found in the GraftJacket group (85%) compared to the control group (40%). American Shoulder and Elbow Surgeons and Constant scores in the GraftJacket group were statistically better at last follow-up.<ref>Barber FA, Burns JP, Deutsch A, Labbe MR, Litchfield RB. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. 2012;28(1):8-15.</ref><ref>Wong I, Burns J, Snyder S. Arthroscopic GraftJacket repair of rotator cuff tears. J Shoulder Elbow Surg. 2010;19(2 Suppl):104-9.</ref>
-Using Synthetic Scaffolds to Augment the Enthesis
+==== Using Synthetic Scaffolds to Augment the Enthesis ====
 Synthetic patch augmentation has shown to protect the repair site and reduce friction in the subacromial space. Ciampi et al. were able to show, in a cohort of 152 patients with posterosuperior tears, a significant decrease in retear rate of 17% in the polypropylene patch augmentation group compared to 51% in the repair-only group at 1-year follow-up, as well as increased abduction strength and elevation at 3-year follow-up.<ref>Ciampi P, Scotti C, Nonis A, Vitali M, Di Serio C, Peretti GM, et al. The benefit of synthetic versus biological patch augmentation in the repair of posterosuperior massive rotator cuff tears: a 3-year follow-up study. Am J Sports Med. 2014;42(5):1169-75.</ref>
-Poly-l-lactic acid bioabsorbable patches designed specifically to reinforce the surgical repair of tendons supported successful repair of large to massive tears in 83% of patients at 12 months after surgery and 78% of patients at 42 months after surgery, with substantial functional improvement<ref>Proctor CS. Long-term successful arthroscopic repair of large and massive rotator cuff tears with a functional and degradable reinforcement device. J Shoulder Elbow Surg. 2014;23(10):1508-13.</ref>
+Poly-l-lactic acid bioabsorbable patches designed specifically to reinforce the surgical repair of tendons supported successful repair of large to massive tears in 83% of patients at 12 months after surgery and 78% of patients at 42 months after surgery, with substantial functional improvement.<ref>Proctor CS. Long-term successful arthroscopic repair of large and massive rotator cuff tears with a functional and degradable reinforcement device. J Shoulder Elbow Surg. 2014;23(10):1508-13.</ref>
 Promising results were also reported when using a bi-layered, absorbable reinforced poly (4)-hydroxybutyrate scaffold that can be used to reinforce rotator cuff reconstruction. Augmenting the tear using this scaffold lead to improved repair integrity of 96% in 50 patients at the 6 month follow-up with no additional failure at the 1 year follow-up.<ref>Barbash S, Denny C, Collin P, Reish T, Hart JM, Brockmeier SF. Clinical Outcomes and Structural Healing After Arthroscopic Rotator Cuff Repair Reinforced With A Novel Absorbable Biologic Scaffold: A Prospective, Multicenter Trial. Orthopaedic Journal of Sports Medicine. 2015;3(2 suppl).</ref>

@@ Line 82: / Line 82: @@
 [[File:1562826768773-lg.jpg|none|thumb|600x600px]]
-==== Leukocyte and platelet-rich plasma (L-PRP) ====
+====Leukocyte and platelet-rich plasma (L-PRP)====
-===== Full Thickness rotator cuff tears =====
+=====Full Thickness rotator cuff tears=====
 Several clinical studies have investigated the application of L-PRP to the reconstruction site. Randelli et al. performed a repair in 53 subjects with 26 of these patients receiving L-PRP augmentation. In the control group (n=27), the rotator cuff was reconstructed without a L-PRP treatment. In the first postoperative month, the L-PRP group showed decreased pain scores and after 3 months an increased simple shoulder test (SST). After 6, 12, and 24 months, no radiographical or clinical differences were reported.<ref>Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011 Jun;20(4):518-28.</ref>
@@ Line 98: / Line 98: @@
 L-PRP injections within interstitial supraspinatus tears did not improve tendon healing or clinical scores compared to saline injections and are associated with more adverse events.<ref>Schwitzguebel AJ, Kolo FC, Tirefort J, Kourhani A, Nowak A, Gremeaux V, Saffarini M, Lädermann A.Efficacy of Platelet-Rich Plasma for the Treatment of Interstitial Supraspinatus Tears: A Double-Blinded, Randomized Controlled Trial. Am J Sports Med. 2019 Jul;47(8):1885-1892.</ref>
-==== Pure platelet-rich plasma (P-PRP) ====
+====Pure platelet-rich plasma (P-PRP)====
-===== Full Thickness rotator cuff tears =====
+=====Full Thickness rotator cuff tears=====
 In a published randomized, single blinded study, 48 patients were randomly assigned to receive either a P-PRP augmented (24 patients) or a conventional (24 patients) rotator cuff reconstruction after large or massive tears. The authors used a leucoreduction plasmapheresis system for the production of P-PRP. The retear rate of the P-PRP group (20.0%) was significantly lower than that of the conventional group (55.6%) (P = .023). Clinical outcomes showed no statistical difference between the 2 groups (all P > .05) except for the overall function (P = .043). The change in the 1-year postoperative and immediately postoperative cross-sectional area (CSA) of the supraspinatus was significantly different between the 2 groups: -15.54 ± 94.34 mm² in the PRP group versus -85.62 ± 103.57 mm² in the conventional group (P = .047). A limitation of this study is the rather small sample size.<ref>Jo CH, Shin JS, Lee YG, Shin WH, Kim H, Lee SY, et al. Platelet-rich plasma for arthroscopic repair of large to massive rotator cuff tears: a randomized, single-blind, parallel-group trial. Am J Sports Med. 2013;41(10):2240-8.</ref>
@@ Line 111: / Line 111: @@
 Another option of augmenting rotator cuff reconstruction is the postoperative injection of platelet concentrates. Autologous conditioned plasma injected in an ultrasound guided manner 7 and 14 days postoperative after reconstruction did not accelerate early tendon healing measured in MRI scans and functional recovery, measured in Quick DASH, Oxford Shoulder Score and VAS compared to a control group.<ref>Wang A, McCann P, Colliver J, Koh E, Ackland T, Joss B, et al. Do postoperative platelet-rich plasma injections accelerate early tendon healing and functional recovery after arthroscopic supraspinatus repair? A randomized controlled trial. Am J Sports Med. 2015;43(6):1430-7.</ref>
-===== Partial Thickness rotator cuff tears =====
+=====Partial Thickness rotator cuff tears=====
 Except for a case report, there is no study investigating the impact of P-PRP on the clinical and radiological outcome of partial thickness tears.
-==== Leukocyte and platelet-rich fibrin (L-PRF) ====
+====Leukocyte and platelet-rich fibrin (L-PRF)====
 =====Full Thickness rotator cuff tears=====
@@ Line 123: / Line 123: @@
 In the 10 patients, where L-PRF was added, an increased vascularization was reported six weeks postoperatively (p= .001) when compared to a control group of patients (n=10), which did not receive L-PRF. Clinical examinations including subjective shoulder value, visual analog scale, Constant, and Simple Shoulder Test scores did not reveal significant differences 6 and 12 weeks postoperatively. A limitation of this study is the rather small sample size. In a subsequent study, 35 patients were randomized to receive arthroscopic reconstruction with L-PRF locally applied to the repair site (n = 17) or without L-PRF (n = 18). They concluded that arthroscopic reconstruction with application of L-PRF yields no beneficial effect in clinical outcome, anatomic healing rate, mean postoperative defect size, and tendon quality at 12 months of follow-up.
-===== Partial Thickness rotator cuff tears =====
+=====Partial Thickness rotator cuff tears=====
 L- PRF is not applicable in partial rotator cuff tears.
-==== Pure platelet-rich fibrin (P-PRF) ====
+====Pure platelet-rich fibrin (P-PRF)====
-===== Full Thickness rotator cuff tears =====
+=====Full Thickness rotator cuff tears=====
 Several authors did not show significant differences in clinical outcome and similar or worst radiographical outcome after application of P-RFM.
@@ Line 137: / Line 137: @@
 Castricini et al. reported no significant difference when comparing the Constant Score (p=0.44) and the rerupture rate (1 of 40 in the P-PRF group, 4/38 in the control group; p=0.07) of the P-PRF and the control group. Also, no difference was found between both groups when comparing the tendon thickness (p=0.18). However, their results are only applicable for small and medium rotator cuff tears.<ref>Castricini R, Longo UG, De Benedetto M, Panfoli N, Pirani P, Zini R, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med. 2011;39(2):258-65.</ref>
-===== Partial Thickness rotator cuff tears =====
+=====Partial Thickness rotator cuff tears=====
 To our knowledge, there is no study investigating the impact of P-PRP on the clinical and radiological outcome of partial thickness tears.
@@ Line 143: / Line 143: @@
 ===Cell Based Augmentation===
-Cells are essential for the healing process of the rotator cuff tears. Tendons are relatively hypocellular. Furthermore, a study by Hernigou et al. has revealed a massive reduction of mesenchymal stem cell levels of up to 70% in bone marrow harvested at the tendon-bone interface of patients with symptomatic tears compared with patients with an intact rotator cuff. The relative lack of cellular machinery in an around the enthesis coupled with poor vascularity results in poor healing potential following acute or overuse injuries[105]. In the recent years, biological augmentation using cell-based therapy has been investigated. The application of stem cells has shown promising results.<ref>46. Hernigou P, Merouse G, Duffiet P, Chevalier N, Rouard H. Reduced levels of mesenchymal stem cells at the tendon-bone interface tuberosity in patients with symptomatic rotator cuff tear. Int Orthop. 2015;39(6):1219-25.</ref>
+Cells are essential for the healing process of the rotator cuff tears. Tendons are relatively hypocellular. Furthermore, a study by Hernigou et al. has revealed a massive reduction of mesenchymal stem cell levels of up to 70% in bone marrow harvested at the tendon-bone interface of patients with symptomatic tears compared with patients with an intact rotator cuff. The relative lack of cellular machinery in an around the enthesis coupled with poor vascularity results in poor healing potential following acute or overuse injuries[105]. In recent years, biological augmentation using cell-based therapy has been investigated. The application of stem cells has shown promising results.<ref>46. Hernigou P, Merouse G, Duffiet P, Chevalier N, Rouard H. Reduced levels of mesenchymal stem cells at the tendon-bone interface tuberosity in patients with symptomatic rotator cuff tear. Int Orthop. 2015;39(6):1219-25.</ref>
 ====Stem Cells to Augment the Enthesis====
-The application of stem cells to the healing site has significant potential as a future therapy. Stem cells can be classified according to their ability to differentiate into other cell types. They can be divided into (1) embryonic stem cells and (2) adult stem cells (Table 4). While totipotent embryonic stem cells from the first couple of cell division cycles can divide into every cell of an organism, pluripotent stem cells lack differentiation into extra-embryonic tissue like the placenta. In contrast, multipotent embryonic stem cells can only divide into a limited range of cells of a single tissue type. Adult stem cells, the second group of stem cells, are multipotent undifferentiated cells found in adult tissue. They include Adipose-derived stem cells (AD-MSC) and Mesenchymal stem cells (MSCs). These cells replace the dying cells in the tissue. Placenta derived stem cells also belong to the adult stem cell group. Unlike MSCs and AD-MSCs, they are pluripotent and have therefore the capacity to differentiate toward all three germ layers.<ref>Miao Z, Jin J, Chen L, Zhu J, Huang W, Zhao J, et al. Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. Cell biology international. 2006;30(9):681-7.</ref>
+The application of stem cells to the healing site has significant potential as a future therapy. Stem cells can be classified according to their ability to differentiate into other cell types. They can be divided into (1) embryonic stem cells and (2) adult stem cells (Table 3). While totipotent embryonic stem cells from the first couple of cell division cycles can divide into every cell of an organism, pluripotent stem cells lack differentiation into extra-embryonic tissue like the placenta. In contrast, multipotent embryonic stem cells can only divide into a limited range of cells of a single tissue type. Adult stem cells, the second group of stem cells, are multipotent undifferentiated cells found in adult tissue. They include Adipose-derived stem cells (AD-MSC) and Mesenchymal stem cells (MSCs). These cells replace the dying cells in the tissue. Placenta derived stem cells also belong to the adult stem cell group. Unlike MSCs and AD-MSCs, they are pluripotent and have therefore the capacity to differentiate toward all three germ layers.<ref>Miao Z, Jin J, Chen L, Zhu J, Huang W, Zhao J, et al. Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. Cell biology international. 2006;30(9):681-7.</ref>
-'''''Classification and characteristics of stem cells'''''
+'''''Table 3. Classification and characteristics of stem cells'''''
 [[File:1562831076306-lg.jpg|none|thumb|600x600px]]
 Even though embryonic stem cells offer a wider therapeutic potential than adult stem cells, especially when using totipotent cells, their use in research is ethically controversial and an increased risk for teratoma development has been reported. When using adult stem cells ethical issues are not as significant and malignant transformations are much less likely.

@@ Line 82: / Line 82: @@
 [[File:1562826768773-lg.jpg|none|thumb|600x600px]]
-Leukocyte and platelet-rich plasma (L-PRP)
+==== Leukocyte and platelet-rich plasma (L-PRP) ====
 Full Thickness rotator cuff tears
 Several clinical studies have investigated the application of L-PRP to the reconstruction site. Randelli et al. performed a repair in 53 subjects with 26 of these patients receiving L-PRP augmentation. In the control group (n=27), the rotator cuff was reconstructed without a L-PRP treatment. In the first postoperative month, the L-PRP group showed decreased pain scores and after 3 months an increased simple shoulder test (SST). After 6, 12, and 24 months, no radiographical or clinical differences were reported.<ref>Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011 Jun;20(4):518-28.</ref>
 Another study, where large and massive tears were augmented using L-PRP also showed no benefit of the L-PRP augmentation except radiographically for smaller iterative tears in the L-PRP group seen in MRI scans. However the clinical outcome measured with the UCLA score, Simple Shoulder Test score, Constant Score and strength was not different in the L-PRP and control group.<ref>Charousset C, Zaoui A, Bellaiche L, Piterman M. Does autologous leukocyte-platelet-rich plasma improve tendon healing in arthroscopic repair of large or massive rotator cuff tears? Arthroscopy. 2014;30(4):428-35.</ref>
-One explanation for these results may be the rather high platelet concentrations. The platelet concentrations in L-PRP is up to 4 times as higher than in physiological blood. There is evidence that platelet concentrations over 2.5-fold result in a reduction in cell proliferation and might therefore have a negative impact on healing.<ref>Graziani F, Ivanovski S, Cei S, Ducci F, Tonetti M, Gabriele M. The in vitro effect of different PRP concentrations on osteoblasts and fibroblasts. Clinical oral implants research. 2006;17(2):212-9.</ref>
+One explanation for these results may be the rather high platelet concentrations. The platelet concentrations in L-PRP are up to 4 times higher than in physiological blood. There is evidence that platelet concentrations over 2.5-fold result in a reduction in cell proliferation and might therefore have a negative impact on healing.<ref>Graziani F, Ivanovski S, Cei S, Ducci F, Tonetti M, Gabriele M. The in vitro effect of different PRP concentrations on osteoblasts and fibroblasts. Clinical oral implants research. 2006;17(2):212-9.</ref>
 Gumina et al. therefore applied platelet-leukocyte membranes, that only allowed 1.7 times greater platelet counts compared to the physiological blood concentrations. They reported improved repair integrity in the L-PRP group compared to the control group, where only a conventional repair was performed (p=.04). However, they did not find any difference with respect to the clinical outcome.<ref>Gumina S, Campagna V, Ferrazza G, Giannicola G, Fratalocchi F, Milani A, et al. Use of platelet-leukocyte membrane in arthroscopic repair of large rotator cuff tears: a prospective randomized study. J Bone Joint Surg Am 2012;94(15):1345-52.</ref>
@@ Line 95: / Line 96: @@
 =====Partial Thickness rotator cuff tears=====
-L-PRP injections within interstitial supraspinatus tears did not improve tendon healing or clinical scores compared with saline injections and are associated with more adverse events.<ref>Schwitzguebel AJ, Kolo FC, Tirefort J, Kourhani A, Nowak A, Gremeaux V, Saffarini M, Lädermann A.Efficacy of Platelet-Rich Plasma for the Treatment of Interstitial Supraspinatus Tears: A Double-Blinded, Randomized Controlled Trial. Am J Sports Med. 2019 Jul;47(8):1885-1892.</ref>
+L-PRP injections within interstitial supraspinatus tears did not improve tendon healing or clinical scores compared to saline injections and are associated with more adverse events.<ref>Schwitzguebel AJ, Kolo FC, Tirefort J, Kourhani A, Nowak A, Gremeaux V, Saffarini M, Lädermann A.Efficacy of Platelet-Rich Plasma for the Treatment of Interstitial Supraspinatus Tears: A Double-Blinded, Randomized Controlled Trial. Am J Sports Med. 2019 Jul;47(8):1885-1892.</ref>
-Pure platelet-rich plasma (P-PRP)
+==== Pure platelet-rich plasma (P-PRP) ====
 Full Thickness rotator cuff tears
 In a published randomized, single blinded study, 48 patients were randomly assigned to receive either a P-PRP augmented (24 patients) or a conventional (24 patients) rotator cuff reconstruction after large or massive tears. The authors used a leucoreduction plasmapheresis system for the production of P-PRP. The retear rate of the P-PRP group (20.0%) was significantly lower than that of the conventional group (55.6%) (P = .023). Clinical outcomes showed no statistical difference between the 2 groups (all P > .05) except for the overall function (P = .043). The change in the 1-year postoperative and immediately postoperative cross-sectional area (CSA) of the supraspinatus was significantly different between the 2 groups: -15.54 ± 94.34 mm² in the PRP group versus -85.62 ± 103.57 mm² in the conventional group (P = .047). A limitation of this study is the rather small sample size.<ref>Jo CH, Shin JS, Lee YG, Shin WH, Kim H, Lee SY, et al. Platelet-rich plasma for arthroscopic repair of large to massive rotator cuff tears: a randomized, single-blind, parallel-group trial. Am J Sports Med. 2013;41(10):2240-8.</ref>
@@ Line 107: / Line 109: @@
 Again, a limitation of this study is the rather small sample size. Similarly, no significant differences were found when applying Autologous Conditioned Plasma or platelet rich plasma prepared by apharesis during reconstruction in two randomized controlled studies.<ref>Malavolta EA, Gracitelli ME, Ferreira Neto AA, Assuncao JH, Bordalo-Rodrigues M, de Camargo OP. Platelet-rich plasma in rotator cuff repair: a prospective randomized study. Am J Sports Med. 2014;42(10):2446-54.</ref><ref>Werthel JD, Pelissier A, Massin P, Boyer P, Valenti P. Arthroscopic double row cuff repair with suture-bridging and autologous conditioned plasma injection: Functional and structural results. Int J Shoulder Surg. 2014;8(4):101-6.</ref>
-Another option of augmenting rotator cuff reconstruction is the postoperative injection of platelet concentrates. Autologous conditioned plasma injected in an ultrasound guided manner 7 and 14 days postoperative after reconstruction did not accelerate early tendon healing measured in MRI scans and functional recovery, measured in Quick DASH, Oxford Shoulder Score and VAS compared to a control group<ref>Wang A, McCann P, Colliver J, Koh E, Ackland T, Joss B, et al. Do postoperative platelet-rich plasma injections accelerate early tendon healing and functional recovery after arthroscopic supraspinatus repair? A randomized controlled trial. Am J Sports Med. 2015;43(6):1430-7.</ref>
+Another option of augmenting rotator cuff reconstruction is the postoperative injection of platelet concentrates. Autologous conditioned plasma injected in an ultrasound guided manner 7 and 14 days postoperative after reconstruction did not accelerate early tendon healing measured in MRI scans and functional recovery, measured in Quick DASH, Oxford Shoulder Score and VAS compared to a control group.<ref>Wang A, McCann P, Colliver J, Koh E, Ackland T, Joss B, et al. Do postoperative platelet-rich plasma injections accelerate early tendon healing and functional recovery after arthroscopic supraspinatus repair? A randomized controlled trial. Am J Sports Med. 2015;43(6):1430-7.</ref>
 Except for a case report, there is no study investigating the impact of P-PRP on the clinical and radiological outcome of partial thickness tears.
-Leukocyte and platelet-rich fibrin (L-PRF)
+==== Leukocyte and platelet-rich fibrin (L-PRF) ====
 =====Full Thickness rotator cuff tears=====
-In-vitro studies showed more constant and longer growth factor release patterns in L-PRF compared to L-PRP and better migration properties of mesenchymal stem cells and entdothelial cells<ref>Schar MO, Diaz-Romero J, Kohl S, Zumstein MA, Nesic D. Platelet-rich concentrates differentially release growth factors and induce cell migration in vitro. Clin Orthop Relat R. 2015;473(5):1635-43.</ref>
+In-vitro studies showed more constant and longer growth factor release patterns in L-PRF compared to L-PRP and better migration properties of mesenchymal stem cells and entdothelial cells.<ref>Schar MO, Diaz-Romero J, Kohl S, Zumstein MA, Nesic D. Platelet-rich concentrates differentially release growth factors and induce cell migration in vitro. Clin Orthop Relat R. 2015;473(5):1635-43.</ref>
 But to date the clinical studies have not demonstrated any benefits with respect to the use of L-PRF. Zumstein et al. augmented the rotator cuff reconstruction in patients using L-PRF in a randomized controlled trial.<ref>Zumstein MA, Rumian A, Lesbats V, Schaer M, Boileau P. Increased vascularization during early healing after biologic augmentation in repair of chronic rotator cuff tears using autologous leukocyte- and platelet-rich fibrin (L-PRF): a prospective randomized controlled pilot trial. J Shoulder Elbow Surg. 2014;23(1):3-12.</ref>
-In the 10 patients, where L-PRF was added, an increased vascularization was reported six weeks postoperative (p= .001) when compared to a control group of patients (n=10), which did not receive L-PRF. Clinical examinations including subjective shoulder value, visual analog scale, Constant, and Simple Shoulder Test scores did not reveal significant differences 6 and 12 weeks postoperative. A limitation of this study is the rather small sample size. In a subsequent study, 35 patients were randomized to receive arthroscopic reconstruction with L-PRF locally applied to the repair site (n = 17) or without L-PRF (n = 18). They concluded that arthroscopic reconstruction with application of L-PRF yields no beneficial effect in clinical outcome, anatomic healing rate, mean postoperative defect size, and tendon quality at 12 months of follow-up.
+In the 10 patients, where L-PRF was added, an increased vascularization was reported six weeks postoperatively (p= .001) when compared to a control group of patients (n=10), which did not receive L-PRF. Clinical examinations including subjective shoulder value, visual analog scale, Constant, and Simple Shoulder Test scores did not reveal significant differences 6 and 12 weeks postoperatively. A limitation of this study is the rather small sample size. In a subsequent study, 35 patients were randomized to receive arthroscopic reconstruction with L-PRF locally applied to the repair site (n = 17) or without L-PRF (n = 18). They concluded that arthroscopic reconstruction with application of L-PRF yields no beneficial effect in clinical outcome, anatomic healing rate, mean postoperative defect size, and tendon quality at 12 months of follow-up.
 L- PRF is not applicable in partial rotator cuff tears.
-Pure platelet-rich fibrin (P-PRF)
+==== Pure platelet-rich fibrin (P-PRF) ====
 Several authors did not show significant differences in clinical outcome and similar or worst radiographical outcome after application of P-RFM.
@@ Line 138: / Line 137: @@
 Castricini et al. reported no significant difference when comparing the Constant Score (p=0.44) and the rerupture rate (1 of 40 in the P-PRF group, 4/38 in the control group; p=0.07) of the P-PRF and the control group. Also, no difference was found between both groups when comparing the tendon thickness (p=0.18). However, their results are only applicable for small and medium rotator cuff tears.<ref>Castricini R, Longo UG, De Benedetto M, Panfoli N, Pirani P, Zini R, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med. 2011;39(2):258-65.</ref>
-Partial Thickness rotator cuff tears
+===== Partial Thickness rotator cuff tears =====
 To our knowledge, there is no study investigating the impact of P-PRP on the clinical and radiological outcome of partial thickness tears.

@@ Line 57: / Line 57: @@
-The ensuing scar tissue formation after repair (Figures 3,4) has a detrimental effect on the biomechanical characteristics of this area compared to the four zones of the physiological enthesis. Hence, there is a strong drive to investigate the role of potential molecular therapies in the form of biological augments that may restore the pathologic enthesis to a near normal physiological state.
+The ensuing scar tissue formation after repair (Figures 3, 4) has a detrimental effect on the biomechanical characteristics of this area compared to the four zones of the physiological enthesis. Hence, there is a strong drive to investigate the role of potential molecular therapies in the form of biological augments that may restore the pathologic enthesis to a near normal physiological state.
 [[File:1562826240385-lg.jpg|center|thumb|600x600px|Figure 3. Subsequent to a repair there is an abnormal enthesis with inferior tissue quality (500 μm).]]
@@ Line 72: / Line 72: @@
 In contrast to the application of growth factors, autologous platelet concentrates are available without the risk associated with allogenic products and they can be prepared during reconstruction. Platelet concentrates have therefore been explored as a promising potential biologic augment for healing. Preclinical in vitro studies have shown promising results, but only a few large-scale clinical studies have investigated its benefit for the healing rotator cuff with inconclusive results.
-The interpretation of the results of these studies is complicated by the fact that there are different platelet concentrates, with varying growth factor release patterns over time. Reasons for these different properties may be found in the lack of standardization between the different platelet concentration systems, with every system containing different concentration of factors and varied activation status of the platelets. Other reasons for inconsistencies between these systems may be due to the different concentrations of other bioactive ingredients such as leukocytes, red blood cells and the fibrinogen. For this reason, Dohan et al. have divided the different platelet concentrates depending on their leukocyte and fibrin content into four categories (Table):<ref>Dohan Ehrenfest DM, Rasmusson L, Albrektsson T. Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends Biotechnol. 2009;27(3):158-67.</ref>
+The interpretation of the results of these studies is complicated by the fact that there are different platelet concentrates, with varying growth factor release patterns over time. Reasons for these different properties may be found in the lack of standardization between the different platelet concentration systems, with every system containing different concentration of factors and varied activation status of the platelets. Other reasons for inconsistencies between these systems may be due to the different concentrations of other bioactive ingredients such as leukocytes, red blood cells and the fibrinogen. For this reason, Dohan et al. have divided the different platelet concentrates depending on their leukocyte and fibrin content into four categories (Table 1):<ref>Dohan Ehrenfest DM, Rasmusson L, Albrektsson T. Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends Biotechnol. 2009;27(3):158-67.</ref>
 #Leucocyte- and platelet-rich plasma (L-PRP) (e.g. GPS III, Magellan and SmartPReP)
@@ Line 79: / Line 79: @@
 #Pure platelet-rich fibrin (P-PRF)(e.g. Cascade FIBRINET PRFM System)
-'''''Platelet-rich concentrates can be divided into four categories depending on their leukocyte and fibrin content. Each group shows different characteristics. The most important ones are depicted in the table.'''''
+'''''Table 2. Platelet-rich concentrates can be divided into four categories depending on their leukocyte and fibrin content. Each group shows different characteristics. The most important ones are depicted in the table.'''''
 [[File:1562826768773-lg.jpg|none|thumb|600x600px]]