Comparison of biomechanical studies of disc repair devices based on a systematic review

Abstract

Background Context:

A variety of solutions have been suggested as candidates for the repair of the annulus fibrosis (AF), with the ability to withstand physiological loads of paramount importance.

Purpose:

The objective of our study was to capture the scope of biomechanical test models of AF repairs. We hypothesized that common test parameters would emerge.

Study design:

Systematic Review

Methods:

PubMed® and EMBASE databases were searched for studies in English including the keywords “disc repair AND animal models”, “disc repair AND cadaver spines”, “intervertebral disc AND biomechanics”, “disc repair AND biomechanics”. This list was further limited to those studies which included biomechanical results from annular repair in animal or human spinal segments from the cervical, thoracic, lumbar and/or coccygeal (tail) segments. For each study, the method used to measure the biomechanical property and biomechanical test results were documented.

Results:

A total of 2,607 articles were included within our initial analysis. Twenty-two articles met our inclusion criteria. Significant variability in terms of species tested, measurements used to quantify annular repair strength, and the method/direction/magnitude that forces were applied to a repaired annulus were found. Bovine intervertebral disc was most commonly used model (6/22 studies) and the most common mechanical property reported was the force required for failure of the disc repair device (15 tests).

Conclusions:

Our hypothesis was rejected; no common features were identified across AF biomechanical models and as a result it was not possible to compare results of pre-clinical testing of annular repair devices. Our analysis suggests that a standardized biomechanical model that can be repeatably executed across multiple laboratories is required for the mechanical screening of candidates for AF repair.

Introduction

Disc herniations can cause focal low back pain and debilitating lumbar radicular symptoms[1, 2]. Low back pain is the top cause for years lived with disability in the United States in 1990–2016[3]. Socio-economic costs for the treatment of low back pain of up to $90 billion have been estimated [4–11]. A proven treatment for symptomatic disc herniation is a discectomy procedure where a portion of a herniated disc is removed allowing for decompression of the thecal sac and exiting nerve roots[12]. 0.5–7.9% of surgeries require revision discectomy due to reherniation[13–16], suggesting continued degeneration of an intervertebral disc/endplate even after a discectomy[17–20]. It has been hypothesized that repairing the annulus fibrosus (AF) might halt the pathophysiology behind disc reherniation after a microdiscectomy[21, 22], but there has yet to be a single device with long term data supporting widespread clinical use[23].

One of the barriers to the widespread use of a disc repair devices is clinical concern over the consequences of displacement of a device within the delicate anatomical space around an intervertebral disc. While numerous devices have been invented to repair defects in the annulus fibrosus, no study has compared results across multiple test systems. This deficiency is particularly important because intervertebral discs plays a vital role in maintaining function and allowing for flexibility within the lumbar spine[24, 25]. The AF experiences loads including tensile, compressive and shear stresses/strains[26, 27]. The lumbar spine, in particular, is at risk for degenerative changes due to the fact that it has a large range of motion and the lordotic alignment of disc spaces places more pressure over the posterior annulus fibrosus during range of motion[28–30]. Further disruption during the lumbar discectomy procedure accelerates intervertebral disc degeneration and may play a role in discogenic back pain[28, 31–33].

The objective of our study was to capture the scope of all biomechanical test models as applied to the intervertebral disc. Our hypothesis was that common test parameters would emerge.

Methods

Study Selection:

The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) methodology was used to prepare our manuscript[34, 35]. Only articles written in English were considered. The PubMed® and EMBASE databases were queried using the search terms “Intervertebral disc AND disc repair AND biomechanics”, “Disc repair AND animal model”, “Disc repair AND human cadaver spine”, “Annulus closure AND spine” or “Intervertebral disc AND disc repair”. A total of 2,607 studies were identified between 1990 to 2018. No abstracts/proceedings from scientific conferences were analyzed within our search process due to insufficient detail within these studies to accurately describe/perform their mechanical testing protocol. We further refined our search to include publications that created mechanically induced disc herniations, and studies that quantified the biomechanical properties of spines treated with a disc repair device. Studies that dealt with a nucleus replacement were not included within this assessment as we were focused on disc repair devices[36–38]. Articles that included only a nucleus replacement without an annular repair were not included in the review.

Analysis of Studies:

Peer reviewed published papers were categorized based on the following criteria: (i) mode of control (ii) dynamic vs. cyclic (iii) apparatus (iv) region of spine (v) species (vi) type of repair and use of a control (vii) primary outcome metric. A master-table was created to capture the scope across the defined categorizations. We paid particular attention to models that were iterated within/across groups. Finally, the limitations of the models in the clinical context of known failure modes and the intended use of candidate materials for AF repair was discussed. The authors have no current direct relationships with companies that produce annular repair devices nor do we have any intellectual property related to annular repair devices.

Results

Articles identified:

Our search terms yielded 2,607 articles. Using our inclusion criteria, 22 articles were identified that had mechanical testing results from an intervertebral annular repair material[21, 22, 28, 39–66]. An overview of our search results is shown in Figure 1. These articles are summarized in Table 1. A breakdown of key conclusions from each article is shown in Table 2.

Figure 1:

The methodology used for our systematic review, resulted in an analysis of 22 papers.

Table 1:

Summary table showing the articles reviewed and highlighting key characteristics of each experiment. Note the wide variety of species tested and primary outcomes from the studies.

					Mode of Control						Cyclic vs static		Apparatus		Region of spine					Primary outcome
Citation	Species	Controltested?	Barrierimplant?	Hydrogel tested?	Axialload/Pressureload	Axialdisplacement	Torque	Torsion angle	Flexion torque	Flexion angle	Dynamic testing	Static testing	Custom apparatus?	Standard apparatus?	Cervical	Thoracic	Lumbar	Tail	Failure	ROM	Stiffness	Displacement	Hydraulic permeability	Adhesion strength	Intradiscal pressure
Ahlgren, 2000 [22]	Sheep	x	x		x							x		x			x		x
Bateman, 2016 [40]	Porcine		x		x					x	x	x		x	x				x
Borde, 2015 [41]	Rat tail	x		x		x						x		x				x			x		x
Bostelman, 2017 [66]	Human	x	x		x				x		x	x	x				x			x					x
Bron, 2010 [42]	Goat	x	x		x					x		x		x			x		x	x
Chiang, 2011 [44]	Porcine		x		x	x					x	x		x	x				x
Chiang, 2012 [45]	Porcine		x		x							x		x			x		x
Frauchiger, 2018 [52]	Bovine	x		x		x						x	x					x			x
Guterl, 2014 [21]	Bovine	x		x		x		x				x	x					x	x					x
Hegewald, 2015 [47]	Sheep	x	x		x							x	x				x		x
Heuer, 2008 [59]	Bovine	x	x		x			x	x		x		x					x	x			x
Kranenburg, 2012 [62]	Canine	x	x	x			x		x			x		x			x			x	x	x
Ledet, 2009 [49]	Sheep	x	x		x							x		x			x		x
Likhitpanichkul, 2015 [53]	Bovine	x		x	x					x		x		x				x		x	x	x
Long, 2016 [55]	Bovine	x		x	x			x		x	x	x	x					x	x	x	x
Long, 2018 [56]	Bovine	x	x		x			x			x	x	x					x	x	x	x			x
Reitmar, 2012 [64]	Sheep	x	x	x	x							x		x			x				x	x
Rickers, 2018 [68]	Porcine	x	x		x			x		x		x		x			x		x	x	x	x		x
Sloan, 2017 [51]	Rat tail	x		x		x						x		x				x			x		x
Vergroessen, 2015 [60]	Goat	x	x		x	x				x	x	x	x	x		x	x		x			x
Wilke, 2013 [67]	Human	x	x		x			x		x	x	x	x				x		x	x		x			x
Yang, 2016 [50]	Porcine	x	x		x							x		x			x		x

Table 2:

Key findings of the included studies on annular repair testing.

Citation	Key Finding
Ahlgren, 2000 [22]	Direct repair of an annular incision does not significantly alter healing strength of an intervertebral disc
Bateman, 2016 [40]	Promising results associated with annular defect closure with a porcine model using 2-0 non-absorbable suture
Borde, 2015 [41]	High density collagen gels may be effective at restoring mechanical function of injured discs
Bostelman, 2017 [66]	Annular closure device restored pressure response of human cadaver discs after discectomy
Bron, 2010 [42]	There were mixed results with an annular closure device in a goat intervertebral disc model
Chiang, 2011 [44]	A modified purse string suture technique can seal a damaged anular defect in a porcine lumbar spine
Chiang, 2012 [45]	A modified purse-string suture technique generates higher contact pressure than other suture techniques
Frauchiger, 2018 [52]	Geinipin-enhanced fibrin hydrogel and an engineered silk scaffold may be used for a intervertebral disc repair
Guterl, 2014 [21]	FibGen gel offers promise for a sealant to repair annulus fibrosus defects
Hegewald, 2015 [47]	Bio-integrative annular implant shows promise as a mechanical barrier in an ovine model
Heuer, 2008 [59]	A promising method for annular repair may be cyanoacrylate glue with suture
Kranenburg, 2012 [62]	A nucleus pulposus prosthesis and suture annular repair helped restore the biomechanical properties of an injured intervertebral disc
Ledet, 2009 [49] Likhitpanichkul, 2015	Using small intestinal submucosa for “patch and plug” repair of annular defects helped maintain hydration and assist in functional recovery of an injured disc
[53]	Injectable Fib-Gen may be able to seal annular fibrosus defects
Long, 2016 [55]	Fibrin-genipin is an easily deliverable adhesive that can fill an irregularly-shaped annular defects
Long, 2018 [56]	Trimethylene carbonate adhesives performed well during in-vitro and in-situ testing as an annular repair material
Reitmar, 2012 [64]	Hydrogels that mimic mechanical behavior of a native nucleus may fail to restore the mechanical behavior of an intervertebral disc
Rickers, 2018 [68]	Repairing an annular defect with polycaprolactone scaffold improves biomechanical behavior
Sloan, 2017 [51]	An injectable riboflavin cross-linked high density collagen gel combined with NP repair with hyaluronic acid hydrogel increased nucleus pulposus hydration
Vergroessen, 2015 [60]	Isocyanate-terminated glue increases the force at which nucleus pulposus protrusion occurs
Wilke, 2013 [67]	Created a human herniation model and found promising results with the Barricaid annular closure device
Yang, 2016 [50]	A modified purse-string suture with an annular graft may increase the integrity of an annulus fibrosis after a punch injury

Region of spine:

Cervical spine testing was done in 2 studies, lumbar spines were tested in 12 studies and 8 studies used tails within their experiment. The most common animal model used was bovine.

Type of annular defect:

Four experiments used two different methods to create annular defects. The smallest defects noted were in rat tails where defects were less than 1mm in length. Canine, porcine and goat models had approximately the same sized defects of 2–4mm in length. Bovine tails and sheep models required slight larger annular defects between 2–5mm in length. The largest defects were used in the two models using human lumbar spines[66, 67]. Nine experiments used a box defect to model an annular injury. The defects created in the annulus within each study are outlined in Table 3.

Table 3:

The range of annular defects created for biomechanical models.

Study	Model	Size of defect	Shape of annular defect	Tissue removed
Ahlgren, 2000 [22]	Sheep	5mm	Transverse incision	Partial discectomy
	Sheep	5mm × 5mm	Cruciate incision	Partial discectomy
	Sheep	5mm × 3mm	Rectangular box	Partial discectomy
Hegewald, 2015 [47]	Sheep	3.5mm × 3.5mm	Square box
Ledet, 2009 [49]	Sheep	4mm × 8mm	Rectangular box
Reitmar, 2012 [64]	Sheep	4mm	Incision	No discectomy or partial discectomy
Bateman, 2016 [40]	Porcine		Vertical incision
Chiang, 2012 [45]	Porcine	4mm	Stab incision
Chiang, 2011 [44]	Porcine	4mm	Transverse incision
Yang, 2016 [50]	Porcine	3mm × 4mm × 11mm	Rectangular box
Rickers, 2018 [68]	Porcine	3mm	Biopsy punch
Borde, 2015 [41]	Rat tail	0.5 mm	21 gaude needle
	Rat tail	1mm × 1mm	Square box
Sloan, 2017 [51]	Rat tail	1mm × 1mm	Square box	Discectomy
Frauchiger, 2018 [52]	Bovine	2mm	Punch biopsy
Guterl, 2014 [21]	Bovine	3mm	Punch biopsy
Likhitpanichkul, 2015 [53]	Bovine	4.5mm × 4.5mm	Square box
Long, 2016 [55]	Bovine	8mm depth	Cruciate incision
	Bovine	5mm	Punch biopsy	30% of nucleus removed
Long, 2018 [56]	Bovine	5mm	Punch biopsy	25% nucleus removed
	Bovine	4mm	Punch biopsy	150–170 mg nucleus/annulus removed
Heuer, 2008 [59]	Bovine		Oblique incision	Nucleotomy
Bron, 2010 [42]	Goat	3mm	Circular defect
Vergroessen, 2015 [60]	Goat	2.4mm	Punch incision
Kranenburg, 2012 [62]	Canine	3–4mm	Stab incision	Nucleotomy
Bostelman, 2017 [66]	Human		6mm × 10mm	Box incision
Wilke, 2013 [67]	Human		6mm × 10mm	Box incision

Apparatus:

Standardized equipment refers to a testing protocol that uses commercially available mechanical testing machines. For example, Sloan et al. used an Enduratec Elf 3200 mechanical testing frame (BOSE, Eden Prarie, MN), while Rickers et al. used an Instron machine (Norwood, MA) [51, 68]. In contrast, Frauchiger et al. used a custom-designed apparatus to place loads over the intervertebral disc[52]. In all, 9/22 studies utilized a custom-built apparatus to perform biomechanical testing. Of note, Vergrosen et al. used a standard testing apparatus to identify the ultimate strength of their device and also used a custom apparatus in order to identify the endurance behavior of their device[60].

Mode of control:

Displacement-controlled systems are programmed to move the loading fixture a certain distance irrespective of the force being applied. Load-controlled systems apply a prescribed load irrespective of the distance the loading fixture travels. Displacement and loadcontrol can be implemented in different directions relative to the anatomy of the cadaveric tissue (Figure 2, Table 1). Axial loading was the most common control mode used in the literature reviewed with load control being used in 15/22 studies, displacement control used in 4/22 studies and 2/22 studies performing both axial load and displacement control testing. Torsional loading around the body of the disc were mainly implemented by applying a defined torsion angle and measuring the required torque to reach that angle (6/22 studies). In the studies that performed flexion testing, the spinal segments were flexed to a defined flexion angle in 7/22 studies while load controlled flexion of spinal segments to a specified torque was used in 3/22 studies.

Figure 2:

Illustration of different modes of control on a segment of the spine. The beige area represents the vertebral body, black lines the annulus and the light grey the nucleus pulposus. The dark grey is the fixture through which force is being applied to the specimen.

Dynamic vs. Static:

Dynamic vs static testing refers to a single load/ displacement was applied (static) or a number of sequential cycles of load/ displacement were applied (cyclic). The majority of studies used a static force (21/22 studies). A significant portion of studies used a dynamic force on the repaired segment (8/22 studies). Seven of the experiments utilized both dynamic and static testing protocols.

Primary outcome metric:

The most common outcome was the force/pressure required for herniation of the disc (15/22 studies), Table 4. Five tests involved needle pressurization of the disc space until material extrusion. Fourteen studies included data on a failure load which represents the magnitude of the force required to disrupt the disc or cause device failure. One study described the failure load for suture loops[43]. One test involved indenting a material with a punch until failure[21]. The values reported and how the disc herniation was detected is outlined in Table 4. The pressure to cause disc herniation ranged from 330 kPa to 10,253 kPa across species. Of note, there was no standardized unit to define the failure force. Certain studies reported failure pressure while others reported failure force. Most often, disc herniation was observed by the human eye, and as such was subjective. In a portion of studies, failure load was also defined as endplate fracture. In 8 studies, a load was placed over the disc space to cause herniation[42, 55, 56, 59, 60, 67, 68]. Three of these studies involved an axial load while 5 studies placed an eccentric load over the disc space with an angled moment. Another common test performed was range of motion before and after disc repair, reported in 8 studies.

Table 4:

Summary of articles that contain failure mechanical testing data for disc repair material. Tests have been grouped together in order to compare how different studies measured and produced a failure load on a repaired disc.

Author	Model	Mechanism of Failure	How did they measure failure?	Force for failure
Ahlgren, 2000 [22]	Sheep	Injected disc and measured pressure at failure	Leakage at annular defect by observer	330 kPa to 1410 kPa
Hegewald, 2015 [47]	Sheep	Injected disc and measured pressure at failure	Leakage at annular defect until contrast leakage by fluoroscopy	530 kPa
Ledet, 2009 [49]	Sheep	Injected disc and measured pressure at failure	Leakage at annular defect until contrast leakage by observer	5,050 kPa
Chiang, 2012 [45]	Porcine	Injected disc and measured pressure at failure	Leaked fluid from annular defect by observer	920–1,700 kPa
Chiang, 2011 [44]	Porcine	Failure of disc/repair with repeated axial compression in static compression and cyclic compressive cycles	Leaked content of disc detected by observer	2,917 N
Yang, 2016 [50]	Porcine	Injected disc and measured pressure at failure	Leakage at annular defect until contrast leakage by observer	1,020 – 4,870 kPa
Long, 2016 [55]	Bovine	20 cycles of from low flexion to 19 deg flexion until herniation detected by a camera after 25% of NP removed	Detected via camera through the loading process	Maximum torque 10.3 +/− 5.9 Nm
Long, 2018 [56]	Bovine	Flexion (0.50 MPa) extension (0.25 MPa) of disc space until herniation detected by a camera	Detected via camera through the loading process	4,500–5,900 kPa
Heuer, 2008 [59]	Bovine	Cyclic off-center loading of 100–600N	Observed herniation of disc material	3400–16,900 cycles until herniation
Bron, 2010 [42]	Goat	Axial compression until extrusion of disc material	Observed herniation of disc material	~1000N to 4000N
Vergroessen, 2015 [60]	Goats	5 deg left lateral flexion until herniation	Observed herniation of disc material	5,500–7,400 kPa
Wilke, 2013 [67]	Human Lumbar	Sinusoidal load until disc failure or 100,000 cycles	Observed herniation of disc material	100–600 N
Rickers, 2018 [68]	Porcine	Axial compression until failure or 4000N	Observed leakage of disc material	300–3100 N
Guterl, 2014 [21]	Bovine	Press fit repair material in annular defect and indented at 0.01mm/s	When repair material fell out of press fit defect	81–146% failure strain

Hydrogel Experiments:

Eight studies examined the performance of a hydrogel for disc repair, see Table 5. Five of these studies employed the hydrogel as an annular repair[21, 41, 52, 53, 55]. Three studies examined biomechanical performance of a nucleus replacement device with a concurrent annular repair strategy included within their experiment[51, 62, 64]. Four of the studies examined the performance of a fibrin-genipin material for annular repair[21, 52, 53, 55]. Two studies used a hyaluronic acid derived hydrogel [51, 64]. Only one of the hydrogels used for disc repair was based off a synthetic molecule[62]. The rest of the hydrogels were derived from organic molecules. Three of the experiments fixated the hydrogel within the disc space with suture to prevent re-herniation. Five of the studies relied on the hydrogel to be “self-adhesive” and to be solidly placed into the disc defect without fixation augmentation devices.

Table 5:

Results from studies that included a hydrogel as a method of fixing an annular defect in an intervertebral disc.

Author, Year	Model	Tested mechanical properties	Hydrogel Description	Attachment of Hydrogel	Origin - synthetic or organic	Crosslinking
Frauchiger, 2018 [52]	Bovine	Stress strain relationship	Genipin-enhanced fibrin hydrogel	Injected then covered with silk-fleece composite	Organic - human fibrinogen	Genipin crosslinks
Likhitpanichkul, 2015 [53]	Bovine	Disc height, Compressive stiffness, Tensile stiffness, Torsional stiffness, Torque range, Stress relaxation time	Fibrin-genipin hydrolgel	Self-adhesive to intervertebral disc	Organic - human fibrinogen	Genipin crosslinks
Long, 2016 [55]	Bovine	Torque stiffness, Torque range, On and off axis stiffness, Maximum torque, Maximum nominal axial stress, Maximum rotation angle, Range of motion, Herniation detected by camera	Fibrin-genipin hydrolgel with poly(trimethyl carbonate) and a polyurethane membrane	Self adhesive and self-adhesive/sutured into place	Organic - human fibrinogen	Genipin crosslinks
Guterl, 2014 [21]	Bovine	Adhesion strength, Adhesive failure	Genipin, Genipin with fibronectin, genipin with collagen and uncrosslinked fibrin gel	Self-adhesive to intervertebral disc	Organic - human fibrinogen	Genipin crosslinks
Kranenburg, 2012 [62]	Canine	Range of motion, Range of angular dislpacement, Disc height, Stiffness (elastic modulus)	4-IEMA, NVP, HEMA and AIBN mixed together then heated for polymerization	Layered closure of muscle/fascia with an annular suture repair (size 4-0)	Synthetic (4-IEMA, NVP, HEMA, AIBN)	Cyclic heating
Reitmair, 2012 [64]	Sheep	Intradiscal pressure, Disc height Change, Compression stiffness	Two hydrogels, DDAHA which is an’ amidic hyaluronic acid derivative and iGG-MA which is an extracellular microbial polysacharide	Annular repair with adhesive glue and sutures	Organic - hyarluronic acid and microbial polysacharide	Gellan gum used for crosslinking for iGG-MA
Sloan, 2017 [51]	Rat Tail	Hydraulic permeability, instantaneous modulus, equilibrium modulus	HYADD4®, hydrogel based on hyaluronic acid derivative	Collagen patch used to fill annular defect through which NP replacement is implanted	Organic - hyaluronic acid derivative	No crosslinking
Borde, 2015 [41]	Rat Tail	Effective equilibirum modulus, Effective instantaneous modulus, Effective hydraulic permeability	High density collagen gel with riboflavin	Injected into annular defect - self-attachment	Organic - Collagen gel	Ribofloxacin crosslinked

The mechanical properties (e.g. stiffness, hydraulic permeability) and function (e.g. range of motion, disc height change) of these hydrogels were tested in 6/8 studies. A measure of the failure of the repair material was only performed in 2/8 studies. In the two studies that performed failure testing, Guterl et al. performed a pushout test of the hydrogel from an annular defect[21]. In situ failure testing was only performed by Long et al. looking at failure of the hydrogel repair in torsion and flexion[55].

Mechanical repairs/barriers for annular defect:

Several studies examined the performance of mechanical barriers for annular repair. Sutures were used either alone or in contrast to other repair strategies (i.e. adhesive glue or hydrogel) in 8 separate studies. Three studies utilized pressure-volume testing where a quantity of fluid was injected within the intervertebral disc to determine the pressure required for disc herniation. Failure load ranged from 1500 kPa – 5650 kPa[22, 45, 50]. Higher failure loads were tolerated in the porcine model as compared to the sheep model.

A custom designed mechanical barrier that included an endplate fixation device was tested in two separate studies[66, 67]. Failure loads and range of motion testing were performed for each experiment where a box annular defect was created and treated with the annular closure device. Schematics from both studies show custom designs for testing each mechanical property.

Fibrin sealant and adhesive glues were used to close an annular defect across three separate animal models with varying mechanical properties tested in each[59, 60, 64]. Long et al. repaired an annular defect with copolymers of polyethylene glycol with varying end-groups and tested varying mechanical properties in a bovine tail[56]. Hegewald et al. tested sheep lumbar spine for the performance of a bio-integrative annulus implant consisting of polyglycolic acid/polyvinylidene fluoride. The failure load for pressure volume testing for the device was 530 kPa[47].

Experimental controls:

Experimental controls were utilized in different manners across studies. Only 3 studies did not use a control. Controls were either defined as an injured disc without repair or a non-injured disc subjected to the same biomechanical testing protocol. All studies which used a control included an injured disc without repair of any kind (19 studies) and the majority of experiments used an uninjured specimen as a control (16/22 studies). In two studies, the control discs and the disc spaces injured/repaired were within the same lumbar spine during testing[22, 49]. Both studies used pressure-volume testing for testing the integrity of the disc space.

Iterations in testing:

Several studies used custom designed models that were modified over many years in their goal of mechanically testing annular closure devices. Ahlgren et al. and Ledet et al. modeled their biomechanical process on the same study by Panjabi et al.[22, 49, 69]. These studies used the same model of injection of fluid within a disc space using different annular repair techniques. Within the original Panjabi et al. study 84 fresh cadaveric specimens were injected with a contrast agent and the maximum/intrinsic pressure was monitored. Yang et al. injected material into a disc to test the integrity of their disc repair device but referenced a separate study by Schechtman et al. when describing their technique[50, 70]. The Schetman et al. and Yang et al. studies monitored disc pressure from above the disc space through the intervertebral body[50, 70]. In a series of studies, Borde et al., Sloan et al. and Bowles et al. described similar mechanical testing protocols for rat tails[41, 51, 71]. They compared equilibrium modulus, effective instantaneous modulus and hydraulic permeability of their collagen gel and/or hydrogel. During tests, a 5% compressive strain was applied in a stepwise fashion until 20% of disc height was reached. The studies by Sloan et al. and Borde et al. are based on an initial study of a nucleus replacement device from the same group[71]. The testing protocol did not seem to change dramatically between studies from 2011–2017.

The biomechanical studies from one group demonstrated significant iterations in terms of biomechanical testing over the span of several years. Guterl et al. used an annular punch method to test adhesion strength of the fibrin-genipin repair material[21]. The next included study from this group included a more complex set of biomechanical testing[53]. The authors of Likhitpanichkul et al. utilized an axial and torsional method of applying force to a motion segment and measured disc height changes, stiffness, range of motion and hysteresis of the repaired disc space[53]. A similar range of mechanical parameters and cycles of force were used to stress the disc repair device in the next study from the group[55]. The most recent study that was included from the group used the same protocol of a preload with cyclic compressive cycles over a motion segment[56]. This last study by Long et al. added an additional data point of a failure mode test with cyclic compression of the disc space until extrusion of a disc as seen by video[56].

Discussion

Our systematic review delineates the current body of literature surrounding the biomechanical performance of annular repair material. We found 22 articles that matched our inclusion criteria. Despite our thorough review, we were unable to delineate common test parameters to simplify comparisons of studies, because there was too much variation in testing methodology and reported results. Given the multidirectional, dynamic loads to which the intervertebral disc is subjected[72], and clinical concern over the severe consequences of failure, we advocate for the development of a clinically relevant, standardized, pre-clinical test-to-failure system, which can be used for the mechanical screening of candidate materials for AF repair.

Our review builds upon previously published review articles on the biomechanics of the spine. Stokes et al. synthesized data on the pathophysiology of disc degeneration with a focus on how abnormal loading, including immobilization, can cause adaptive changes within an intervertebral disc[73]. Weber et al. described the molecular changes that occur with disc degeneration and regeneration as well as offering a broad overview of hydrogels and annular repair devices[74]. Inoue et al. reviewed the biomechanical changes associated with disc degeneration[75], while both Alini et al. and Long et al. reviewed biomechanical requirements of annular repair devices[28, 76]. We have built upon these reviews by specifically analyzing biomechanical test systems and approaches as applied to annular repair devices to provide a unique perspective on the challenges that clinicians face when trying to decipher the various test systems and results presented in literature. For instance, unlike other systematic reviews, it is difficult to create a useful forest plot of results from each study given the wide variety of primary outcome measures, species tested, testing apparatus, etc. used among all the studies included within the review. The authors acknowledge, however, that a limitation of our study is that we are not outlining/defining deficiencies of each of our included studies.

Although modeling a complex clinical situation like a disc herniation is difficult, it is a particularly important consideration when attempting to create a defect across which the biomechanical performance of an annular repair device can be reliably characterized. The degeneration of the disc itself is in large part cause by genetic factors which make some disc herniations destine to herniate[77]. Disc degeneration may also be induced from prolonged exposure to whole body vibration[78]. To circumvent the insurmountable challenges of replicating a lifetime of vibration on a disc space or the intrinsic genetic factors, we found that defects were created in a wider variety of ways using punch biopsies, needle punctures, transverse incisions, and box incisions. With such varied incisions, the mechanical effect on candidate repair devices is likely to reflect that variability. Establishing a simple and reproducible defect to both create an annular defect and extrude an intervertebral disc will be vital to allow for cross comparison of studies.

The proximity of nerve roots and thecal sac posteriorly as well as the great vessels anteriorly makes it critically important to ensure a disc repair device does not fail under the most severe biomechanical environment. Any displacement or fragmentation of the device could mean dire consequences for a patient. For instance, cases of posterior migration of an interbody cage after a transforaminal lumbar interbody fusion cage insertion which resulted in a return to the operating room and nerve injury, have been reported[79]. Given the potentially severe consequences of mechanical failure, and the risks of translating devices to clinical use without preempting all possible modes of failure[80, 81], pre-clinical biomechanical testing that mimics expected modes of failure is crucial. Therefore, it is not surprising that the most commonly tested parameter was failure force for a device. Unfortunately, cross comparisons of the results from testing-to-failure is not straightforward. A myriad of factors and relationships that must be delineated in order to understand what a failure force means in the context of an experiment, Figure 3. Each of the factors listed must be controlled for within an experiment to understand how one group’s results compare to another group’s results with similar or different annular repair device.

Figure 3:

The factors that should be clearly defined in a failure test. If a failure test is created, scaling factors must be outlined if a different species or if a different region of the spine is tested.

A cross section of standard, commercailly available and customized test systems were used to test the biomechanical properties of annular repair devices. Thirteen studies used a standard testing apparatus and 9 studies used a custom built apparatus. It is valid to use a custom apparatus for these biomechanical tests as long as the description provided within a study is clear enough to be replicated. Both Long et al. and Bostelman et al. have detailed “Methods” sections that outline pieces of equipment required and how to setup thes testing protocol[56, 66]. Photos of setups also help guide future researchers to replicate testing conditions[66]. In our detailed reading of the methodology of all 9 of these apparatuses, 2/9 of these tests we felt lacked enough clarity to reliably create a replicate apparatus[47, 60]. Other studies outlined testing apparatuses that were complex and would likely require significant time/resources from an experienced mechanical engineer[52, 59]. Whatever testing becomes uniformly accepted as a “gold standard” must be reproducible, validated and replicated in multiple labs and allow researchers to easily setup and administer.

Amongst all studies substantial variability in species tested and the region of the spine tested was noted. As described by Alini et al. scaling of results from animal species and different regions of the spine is not straightforward for a number of reasons[76]. These include the significant variation in the geometry of discs, patterns of annular fibers, orientation of stabilizing facet joints and the biology of discs. Future research is required to understand how one biomechanical test performs on different models and different regions of the spine. Moreover, as advancements in cell therapies for intervertebral disc degeneration continue further research will also be required in the biomechanical behavior of these repaired discs. Reconstituting native tissue may be the eventual goal but testing whether this newly created tissue is comparable to native disc spaces will need to validated[82]. We strongly encourage scientists experimenting with these cell-based therapies pay special care to understand and test out the biomechanical properties of their therapy to ensure safe usage within humans.

In summary, while there have been extensive scientific advancements in design of compounds/barriers to repair a disc, the lack of standardized, reproducible biomechanical test systems that are widely accepted as a benchmark for disc repair material is a barrier to clinical translation. The authors propose that a simplified and scientific based platform for standardized testing of disc repair devices be designed for both animal and human cadaver spines. Widespread use of this standardized protocol would allow movement from bench top research to eventual clinical trials for promising annular repair products.

Clinical Significance:

This literature review provides a summary of pre-clinical testing of annular repair devices for clinicians to properly evaluate the safety/efficacy of developing technology designed to repair annular defects after disc herniations.