Biological approaches to the repair and regeneration of the rotator cuff tendon-bone enthesis: a literature review

doi:10.12336/biomatertransl.2023.02.004

Biomaterials Translational ›› 2023, Vol. 4 ›› Issue (2): 85-103.doi: 10.12336/biomatertransl.2023.02.004

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Biological approaches to the repair and regeneration of the rotator cuff tendon-bone enthesis: a literature review

Ahlam A. Abdalla¹^,^*(), Catherine J. Pendegrass²^,^*()

1 Institute of Sport, Exercise and Health (ISEH), Division of Surgery & Interventional Sciences, University College London, London, UK
2 Department of Orthopaedics & Musculoskeletal Science, Division of Surgery & Interventional Sciences, University College London, Brockley Hill, Stanmore, UK

Received:2023-02-04 Revised:2023-03-15 Accepted:2023-05-05 Online:2023-06-28 Published:2023-06-28
Contact: Ahlam A. Abdalla,Catherine J. Pendegrass E-mail:ahlam.abdalla.21@ucl.ac.uk;c.pendegrass@ucl.ac.uk
About author:Catherine J. Pendegrass, c.pendegrass@ucl.ac.uk.
Ahlam A. Abdalla, ahlam.abdalla.21@ucl.ac.uk;
First author contact:
†Present Addresses: Department of Orthopaedics & Musculoskeletal Science, Division of Surgery & Interventional Sciences, University College London, Brockley Hill, Stanmore, UK

Abstract

Abstract:

Entheses are highly specialised organs connecting ligaments and tendons to bones, facilitating force transmission, and providing mechanical strengths to absorb forces encountered. Two types of entheses, fibrocartilaginous and fibrous, exist in interfaces. The gradual fibrocartilaginous type is in rotator cuff tendons and is more frequently injured due to the poor healing capacity that leads to loss of the original structural and biomechanical properties and is attributed to the high prevalence of retears. Fluctuating methodologies and outcomes of biological approaches are challenges to overcome for them to be routinely used in clinics. Therefore, stratifying the existing literature according to different categories (chronicity, extent of tear, and studied population) would effectively guide repair approaches. This literature review supports tissue engineering approaches to promote rotator cuff enthesis healing employing cells, growth factors, and scaffolds period. Outcomes suggest its promising role in animal studies as well as some clinical trials and that combination therapies are more beneficial than individualized ones. It then highlights the importance of tailoring interventions according to the tear extent, chronicity, and the population being treated. Contributing factors such as loading, deficiencies, and lifestyle habits should also be taken into consideration. Optimum results can be achieved if biological, mechanical, and environmental factors are approached. It is challenging to determine whether variations are due to the interventions themselves, the animal models, loading regimen, materials, or tear mechanisms. Future research should focus on tailoring interventions for different categories to formulate protocols, which would best guide regenerative medicine decision making.

Key words: enthesis, rotator cuff, stem cells, tissue engineering, tendon-bone enthesis

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Author	Study	Model	Tear	Intervention	Outcome measure	Results
Honda et al.⁶⁸	In-vivo	Rabbit	Chronic full	MSC + HA	Biomechanical, histological, and immunohistochemical analyses	Positive: Improved ultimate load and faster healing
Jo et al.⁶⁹	Clinical	Human	Chronic full	BMSC + arthroscopic repeated channeling	Pain scale, ROM, muscle strength, patient satisfaction questionnaire, and functional scores. Structural integrity by MRI and CT	Positive: Enhanced structural integrity of the repair and decreased retears
Hernigou et al.⁷⁰	Clinical	Human	Chronic partial	BMSC + arthroscopy	MRI	Positive: Faster complete healing/retear prevention
Taniguchi et al.⁷¹	Clinical	Human	Chronic partial	ASH + BMSC	MRI	Positive: Reduced retear rates/better integrity
Han et al.⁷²	In-vitro, in-vivo	Rat	Acute full	PRP-infused BMSC	Expression of genes that related to tissue repair, bone formation, and tendon regeneration;	Positive: Stronger signals to angiogenesis, bone formation, and tendon generation in-situ
					Biomechanical assessment	Promoted healing in-vivo
Gulotta et al.⁷³	In-vivo	Rat	Acute full	BMSC	Biomechanical & histological analyses	Negative: No change in structure, composition, or strength
Gulotta et al.⁷⁵	In-vivo	Rat	Acute full	MT1-MMP-transduced MSCs	Biomechanical & histological analyses	Positive: Better fibrocartilage formation, higher ultimate load and stress to failure, and higher stiffness
Oh et al.⁷⁷	In-vivo	Rabbit	Chronic full	ADSC + suture	Electromyographic, biomechanical & histological analyses	Positive: Larger load to failure and less fat infiltration
Chen et al.⁷⁸	In-vivo	Murine	Acute full	ADSC imbedded in fibrin sealant scaffold	Biomechanical & histological analyses	Positive: Better biomechanical strength and histological score
Choi et al.⁷⁹	In-vivo	Rat	Chronic full	ADSC sheets interposed at the enthesis	Biomechanical & histological analyses	Positive: Successful complete regeneration and biomechanical strength
Valencia Mora et al.⁸⁰	In-vivo	Rat	Chronic full	ADSC, ADSC + TGF-β3	Biomechanical & histological analyses	Positive: Reduced inflammation
						Negative: Unchanged maximum load, elastic energy, mechanical deformation, and stiffness

Author	Study	Model	Tear	Intervention	Outcome measure	Results
Honda et al.⁶⁸	In-vivo	Rabbit	Chronic full	MSC + HA	Biomechanical, histological, and immunohistochemical analyses	Positive: Improved ultimate load and faster healing
Jo et al.⁶⁹	Clinical	Human	Chronic full	BMSC + arthroscopic repeated channeling	Pain scale, ROM, muscle strength, patient satisfaction questionnaire, and functional scores. Structural integrity by MRI and CT	Positive: Enhanced structural integrity of the repair and decreased retears
Hernigou et al.⁷⁰	Clinical	Human	Chronic partial	BMSC + arthroscopy	MRI	Positive: Faster complete healing/retear prevention
Taniguchi et al.⁷¹	Clinical	Human	Chronic partial	ASH + BMSC	MRI	Positive: Reduced retear rates/better integrity
Han et al.⁷²	In-vitro, in-vivo	Rat	Acute full	PRP-infused BMSC	Expression of genes that related to tissue repair, bone formation, and tendon regeneration;	Positive: Stronger signals to angiogenesis, bone formation, and tendon generation in-situ
					Biomechanical assessment	Promoted healing in-vivo
Gulotta et al.⁷³	In-vivo	Rat	Acute full	BMSC	Biomechanical & histological analyses	Negative: No change in structure, composition, or strength
Gulotta et al.⁷⁵	In-vivo	Rat	Acute full	MT1-MMP-transduced MSCs	Biomechanical & histological analyses	Positive: Better fibrocartilage formation, higher ultimate load and stress to failure, and higher stiffness
Oh et al.⁷⁷	In-vivo	Rabbit	Chronic full	ADSC + suture	Electromyographic, biomechanical & histological analyses	Positive: Larger load to failure and less fat infiltration
Chen et al.⁷⁸	In-vivo	Murine	Acute full	ADSC imbedded in fibrin sealant scaffold	Biomechanical & histological analyses	Positive: Better biomechanical strength and histological score
Choi et al.⁷⁹	In-vivo	Rat	Chronic full	ADSC sheets interposed at the enthesis	Biomechanical & histological analyses	Positive: Successful complete regeneration and biomechanical strength
Valencia Mora et al.⁸⁰	In-vivo	Rat	Chronic full	ADSC, ADSC + TGF-β3	Biomechanical & histological analyses	Positive: Reduced inflammation
						Negative: Unchanged maximum load, elastic energy, mechanical deformation, and stiffness

Author	Study	Model	Tear	Intervention	Outcome measure	Study results
Zong et al.⁸²	In-vivo	Rat	Acute full	Ihh + MSC	Immunohistochemical staining and proliferating cell nuclear antigen staining	Positive: Increased Gli1 and Patched1 expression. More organised and stronger staining for collagen II
Schwartz et al.²⁹	In-vivo	Murine	Acute partial	Ihh	Lineage tracing	Positive: Gli1 lineage cells that originate in utero eventually populate the entire mature enthesis. Ablation of the Hh-responsive cells during the first week of postnatal development resulted in a loss of mineralised fibrocartilage
Schwartz et al.⁸³	In-vivo	Mouse	Acute partial	Ihh	Lineage tracing	Positive: High levels of Gli1 expression in immature mice and mature entheses had fewer Gli1⁺ cells
Hettrich et al.⁸⁷	In-vivo	Rat	Acute full	Systemic PTH	Histologic, immunohistochemical, biomechanical analyses	Positive: Higher stiffness, bone volume and mineral content; More fibrocartilage, osteoblasts, and blood vessels formation; Better collagen orientation
Duchman et al.⁸⁸	In-vivo	Rat	Acute full	Systemic rhPTH	Biomechanical and histologic analysis	Positive: Higher load to failure. Expression of intracellular and extracellular VEGF
Oh et al.⁸⁹	Clinical	Human	Chronic full	Systemic rhPTH	MRI, ROM, American Shoulder and Elbow Surgeons and Constant scores, and simple shoulder test	Positive: Lower retear rate

Author	Study	Model	Tear	Intervention	Outcome measure	Study results
Zong et al.⁸²	In-vivo	Rat	Acute full	Ihh + MSC	Immunohistochemical staining and proliferating cell nuclear antigen staining	Positive: Increased Gli1 and Patched1 expression. More organised and stronger staining for collagen II
Schwartz et al.²⁹	In-vivo	Murine	Acute partial	Ihh	Lineage tracing	Positive: Gli1 lineage cells that originate in utero eventually populate the entire mature enthesis. Ablation of the Hh-responsive cells during the first week of postnatal development resulted in a loss of mineralised fibrocartilage
Schwartz et al.⁸³	In-vivo	Mouse	Acute partial	Ihh	Lineage tracing	Positive: High levels of Gli1 expression in immature mice and mature entheses had fewer Gli1⁺ cells
Hettrich et al.⁸⁷	In-vivo	Rat	Acute full	Systemic PTH	Histologic, immunohistochemical, biomechanical analyses	Positive: Higher stiffness, bone volume and mineral content; More fibrocartilage, osteoblasts, and blood vessels formation; Better collagen orientation
Duchman et al.⁸⁸	In-vivo	Rat	Acute full	Systemic rhPTH	Biomechanical and histologic analysis	Positive: Higher load to failure. Expression of intracellular and extracellular VEGF
Oh et al.⁸⁹	Clinical	Human	Chronic full	Systemic rhPTH	MRI, ROM, American Shoulder and Elbow Surgeons and Constant scores, and simple shoulder test	Positive: Lower retear rate

Author	Study	Model	Tear	Intervention	Outcome measure	Study results
Würgler-Hauri et al.¹⁰⁵	In-vivo	Rat	Acute full	BMP-12-14, bFGF, COMP, CTGF, PDGFB, TGF-β1	Immunohistochemical staining	Positive: Increase in the expression of all GFs at 1 week, and followed by a return to control or undetectable levels by 16 weeks
Kobayashi et al.¹⁰⁶	In-vivo	Rabbit	Acute full	BMP-12-14, bFGF, COMP, CTGF, PDGFB, TGF-β1	Light microscopy after staining with hematoxylin-eosin and Elastica-Masson; Immunohistochemical staining	Positive: GFs are involved in early phases of healing promotion
Rodeo et al.¹⁰⁷	In-vivo	Sheep	Acute full	BMP and VEGF	MRI, plain radiographs, histologic analysis, and biomechanical testing	Positive: Greater formation of new bone, fibrocartilage, and soft tissue, with an increase in tendon attachment strength
Angeline and Rodeo⁴³	In-vivo	Sheep	Acute full	BMP and VEGF	Histologic analysis	Positive: Induced angiogenesis and vasculogenesis. Faster and better recovery
Manning et al.¹¹⁰	In-vivo	Rat	Acute full	TGF-β3	Histologic and biomechanical analyses	Negative: Disorganised scar and inferior mechanical properties
Kim et al.¹⁰⁸	In-vivo	Rat	Acute full	TGF-β3	Histologic and biomechanical analyses	Negative: Disorganised scar and inferior mechanical properties
Davies et al.¹¹²	In-vivo	Mouse	Acute full	Inhibiting TGF-β1	Histologic analysis	Positive: Reduced fibrosis, fatty infiltration, and muscle atrophy
Jensen et al.³²	In-vivo	Mouse	Acute full and partial	TGF-β3 + cytokine + MMP inhibitors	Reviewing the literature	Positive: Enhanced healing
Zhou et al.¹¹³	In-vivo	Rat	Acute full	rhFGF-18	Histologic analysis	Positive: Promoted chondrogenesis and promoted healing and regeneration
Sitcheran et al.¹¹⁴	In-vivo	Mouse	Acute full	TGF-β3	Histologic analysis	Negative: No improvement in healing
Gulotta et al.¹¹⁵	In-vivo	Rat	Acute and chronic full	TNF inhibitor	Histologic and biomechanical analyses	Positive: Elevated fibrocartilage, and enhanced load to failure and stiffness
Dorman et al.¹¹⁷	In-vivo	Mouse	Acute full	BMP-2-7	Histologic analysis	Positive: Fully healed enthesis without toxicity
Kabuto et al.¹¹⁸	In-vivo	Rat	Acute full	BMP-2-7	Histologic and biomechanical analyses	Positive: Improved biomechanical properties

Biological approaches to the repair and regeneration of the rotator cuff tendon-bone enthesis: a literature review

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Author	Study	Model	Tear	Intervention	Outcome measure	Study results
Huang et al.¹²⁴	In-vivo	Rabbit	Acute full	KGN-loaded GelMA hydrogel + BMSC scaffold	Macroscopy, microcomputed tomography, histology, and biomechanical tests	Positive: Promoted fibrocartilage formation and superior mechanical properties
Novakova et al.⁹³	In-vivo	Sheep	Acute full	Engineered tendon construct with BMSCs	X-ray and biomechanical tests	Positive: Native-like enthesis with higher modulus
Han et al.¹²⁵	In-vivo	Rabbit	Acute full	BMP-2 + polyaspartic acid + Smad/RUNX2 signaling	Transmission electron microscopy staining; Biomechanics and histological assessment	Positive: Increased bone and tissue mineral density and ultimate load strength
Ousema et al.¹²⁶	In-vitro	RC tear		3D woven PCL scaffold + IL-1 inhibition on MSCs	Histological, biomechanical, and immunohistochemistry analyses	Positive: Mechanical functionality preserved with the use of a 3D woven PCL scaffold
Jiang et al.¹²⁷	In-vitro	RC tear		3D PLGA scaffold + a cell-laden collagen hydrogel + ADSCs	Histological and biomechanics analyses	Positive: Improvement in mechanical properties and biocompatibility
Iannotti et al.¹³¹	Clinical	Human	Chronic full	SIS	Penn shoulder-score questionnaire and MRI	Negative: No improvement in healing and clinical results
Malcarney et al.¹³²	Clinical	Human	Chronic full	SIS	Study discontinued due to adverse effects	Negative: Inflammatory reaction
Sclamberg et al.¹³⁰	Clinical	Human	Chronic full	SIS	Patient questionnaire, MRI, and ASES	Negative: No improvement and worse pot-operative outcomes
Ciampi et al.¹²⁸	Clinical	Aging human	Chronic full	Polypropylene augmentation patch	Ultrasound, muscle strength, and VAS	Positive: Improved muscle strength, pain score, and tendon integrity
Cai et al.¹²⁹	Clinical	Aging human	Chronic full	3D biological collagen-I mesh	MRI, VAS, UCLA SST, and Constant score	Positive: Less retear rates
Hoberman et al.¹³³	In-vitro	RC tear		DBM + BMSCs + PRP	Adhesion, proliferation, and differentiation assays	Positive: Better adhesion, proliferation, and differentiation
Thangarajah et al.¹³⁴	In-vivo	Rat	Chronic full	DBM	Histological analysis	Negative: No improvement in collagen organisation and fibrocartilage formation
Thangarajah et al.¹³⁵	In-vivo	Rat	Chronic full	DBM + MSCs	Histological analysis	Positive: Enhanced healing
Smith et al.¹³⁶	In-vivo	Canine	Chronic full	PRP + DBM	Histological and biomechanical analysis	Positive: Improvement in strength and histological structure
Wellington et al.¹³⁷	Clinical	Human	Chronic full	DBM + MSCs	MRI	Negative: Supraspinatus failure
Chae et al.¹³⁸	In-vivo	Mouse	Chronic full	3D cell-printed tendon-bone interface construct	>Gait analysis, histological and biomechanical analysis	Positive: Fully formed enthesis, improved shoulder outcome and biomechanical properties
Yoon et al.¹³⁹	Clinical	Aging and young human	Chronic full	ADF	ROM, VAS, and MRI	Positive: No adverse effects, improved VAS, and functional scores
Warth et al.¹⁴¹	Clinical	Human	Chronic full	PRP	MRI and Constant score	Positive: Lower retear and improved constant score
Castricini et al.¹⁴²	Clinical	Human	Chronic partial	Autologous PRFM	MRI	Positive: Improved tendon integrity
			Chronic full	Autologous PRFM	MRI	Negative: No difference in constant score and tendon integrity
Giovannetti de Sanctis et al.¹⁴⁴	Systematic review	Human	Chronic partial	PRP	Shoulder function and VAS	Positive: Improved pain and shoulder function
Von Wehren et al.¹⁴⁵	Clinical	Human	Chronic partial	PRP	MRI, Constant score, ASES, shoulder ROM, and VAS	Positive: Improved pain and function
Xu and Xue¹⁴⁶	Systematic review	Human	Chronic full	PRP	Retear rate, Constant, UCLA, ASES, VAS, and adverse effects	Positive: Improved shoulder outcome and reduced retear rate
Rha et al.¹⁴⁷	Clinical	Human	Chronic partial	PRP	Shoulder Pain and Disability Index, ROM, and ultrasound	Positive: No adverse effects, and improved shoulder pain and function
Shams et al.¹⁴⁸	Clinical	Human	Chronic partial	PRP	MRI, ASES, Constant Score, SST, and VAS	Positive: Improved shoulder function and minor MRI improvement
Cai et al.¹⁴⁹	Clinical	Young human	Acute partial	SH + PRP	VAS, Constant score, and MRI	Positive: Better VAS, constant score, and MRI findings
Ryan et al.¹⁵⁰	Systematic review	Human	Chronic full	PRP	Constant, ASES, UCLA, SST, VAS, and retear rate	Positive: Reduced retear rates and improved clinical outcomes
Lavoie-Gagne et al.¹⁵¹	Systematic review and meta-analysis	Human	Chronic full	PRP	Clinical characteristics, retear rates, ROM, and patient reported outcomes	Positive: Reduced retear rates and improved clinical outcomes
Ilhanli et al.¹⁵²	Clinical	Human	Chronic partial	PRP	ROM, VAS, Disabilities of Arm, Shoulder and Hand questionnaire, Neer's, Hawkins' and drop arm tests and Beck Depression Inventory questionnaire	Negative: Results were not superior to physiotherapy

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