Sage Journals: Discover world-class research

Abstract

Objective

Despite the mechanical and biological roles of subchondral bone (SCB) in articular cartilage health, there remains no consensus on the postoperative morphological status of SCB following bone marrow stimulation (BMS). The purpose of this systematic review was to clarify the morphology of SCB following BMS in preclinical, translational animal models.

Design

The MEDLINE and EMBASE databases were systematically reviewed using specific search terms on April 19, 2016 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The morphology of the SCB was assessed using of microcomputed tomography (bone density) and histology (microscopic architecture).

Results

Seventeen animal studies with 520 chondral lesions were included. The morphology of SCB did not recover following BMS. Compared with untreated chondral defects, BMS resulted in superior morphology of superficial SCB and cartilage but inferior morphology (specifically bone density, P < 0.05) of the deep SCB. Overall, the use of biological adjuvants during BMS resulted in the superior postoperative morphology of SCB.

Conclusions

Alterations in the SCB following BMS were confirmed. Biologics adjuvants may improve the postoperative morphology of both SCB and articular cartilage. Refinements of BMS techniques should incorporate consideration of SCB damage and restoration. Investigations to optimize BMS techniques incorporating both minimally invasive approaches and biologically augmented platforms are further warranted.

Keywords

animal models bone marrow stimulation systematic review subchondral bone

Introduction

The treatment of symptomatic cartilage defects remains challenging despite intense focus from the orthopaedic and scientific communities. Bone marrow stimulation (BMS) is considered the first-line treatment for symptomatic cartilage defects because of its minimally invasive approach, cost-effectiveness, and limited surgical morbidity¹; it is also considered a gold standard for comparison of emerging cartilage repair technologies.² BMS techniques (microfracture and/or drilling) stimulate cartilage healing by directly accessing the regenerative elements of bone marrow by penetrating the subchondral bone (SCB) directly from within the defect.³ The resultant regenerative mesenchymal clot contains stem cells and growth factors that support the formation of fibrocartilage within the defect. Patient-reported outcomes have shown significant improvement following marrow stimulation in the short to medium term with a progressive decline in the performance of the repair tissue in the medium to long term. Inferior biomechanical properties of fibrocartilage and postinjury joint homeostasis have been implicated.^3-6

The SCB consists of a superficial plate and deep spongy bone that performs important mechanical and biological roles to support and maintain the overlying cartilage.^7-11 The SCB is known to absorb 70% of compressive loads mechanically and have cross-talk with the articular cartilage, communicating biochemical signals through transport pathways between them.⁷ Contextually, it is currently unclear if the surgical trauma required during BMS procedures (removal of the calcified cartilage layer and penetration of the SCB) is recoverable. Given the importance of SCB in cartilage health,^7-11 persistent deficits in its structure may affect the quality and sustainability of the repair tissue.¹²

The purpose of this systematic review was to clarify the morphology of SCB following BMS in preclinical, translational animal models.

Methods

Search Strategy

Two independent reviewers performed a systematic review of the MEDLINE and EMBASE databases in April 19, 2016 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹³

The search terms were: (subchondral bone plate OR subchondral bone plate over growth OR subchondral bone plate remodeling OR osteocartilage regeneration OR osteocartilage repair OR tidemark) AND (bone marrow stimulation OR microfracture OR drilling OR abrasion). References of all searched articles were also screened for possible inclusion. The inclusion and exclusion criteria are shown in Table 1 .

Table 1.

Inclusion and Exclusion Criteria.

Inclusion criteria

Intervention included the use of bone marrow stimulation ± adjuvants

Comparative studies

Animal studies

Published in a peer-review journal

Written in English

Exclusion criteria

Clinical studies

Human cadaver studies

In vitro studies

Review studies

Two independent reviewers screened the titles, abstracts and full-text articles of all searched studies by applying the aforementioned criteria. Any disagreements were resolved by consensus and if disagreement persisted, a senior author was consulted ( Fig. 1 ).

Figure 1.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram.

Data Evaluation

A standardized sheet was used to extract predetermined variables. The methodological quality of evidence (QoE) was evaluated using the Modified Horn Scale ( Table 2 ).¹⁴ This is an 8-point scale designed to evaluate the QoE in animal studies. Each criterion was worth 0 or 1 point; 1 point was awarded when the study reports the criteria being mentioned. Studies scoring <4 points were graded as having poor QoE and studies with ≥4 points were graded as having good QoE.

Table 2.

Modified Horn Scale.

Modified Horn Criteria
1	Comparison of sizes or depths/awls vs. drills for BMS ± adjuvant dose to response relationship
2	Randomization of the experiment
3	Peer-review publication
4	Control of the animal’s physiological parameters
5	Blinded outcome assessment
6	Assessment of at least 2 outcomes (e.g., µCT and histology)
7	Assessment in the acute phase (≤1 month)
8	Assessment in the chronic phase (≥6 months)

BMS, bone mallow stimulation; µCT, microcomputed tomography.

The included studies were categorized into 2 groups based on the character of the chondral lesion: (1) full-thickness chondral defect treated with BMS (BMS group) versus full-thickness chondral defect untreated (untreated group) and (2) BMS group versus full-thickness chondral defect treated with BMS + adjuvants (BMS-A group). Studies were then divided according to their time(s) until evaluation into 3 time phases: acute (0 to 2 weeks), subacute (2 weeks to 3 months) and late (≥6 months). Individual morphological assessment was then made according to the various anatomical parts of SCB: deep SCB and superficial SCB. This included microcomputed tomography (µCT) to assess the bone densities and histology to assess microscopic architectures.

SCB and Cartilage Assessment

µCT assessments were made only for the SCB and was divided into deep and superficial components according to previously published criteria.¹⁵ The deep SCB was assessed using “bone volume over total volume” (BV/TV; %) and the superficial SCB was assessed using “bone surface area over bone volume” (BS/BV; mm⁻¹). Both these are measurements of bone densities of the deep SCB and superficial SCB, respectively. Assessments of superior/inferior µCT results were made within the study and generalized across the included studies.

Histological assessments were made for both SCB and cartilage according to various reported grading systems within individual studies (American Association of Equine Practitioners lameness scale, histomorphometry, immunohistochemistry, International Cartilage Repair Society II score, O’Driscoll score, Modified O’Driscoll score and Sanz score). Assessments of superior/inferior histological assessments were made within the study first; trends were then generalized across the included studies. Histological assessments of the deep SCB and superficial SCB were defined anatomically.⁷ Histological assessment of the deep SCB was noted when microscopic architectural assessment of the spongy bone was made and histological assessment of the superficial SCB was noted when microscopic architectural assessment of the bone plate was made.

Definition of Morphology

Morphology of the SCB referred to its structural components assessed by µCT and/or histology. In histological analysis, superior morphology of cartilage referred to increased hyaline-like repair with inferior morphology of cartilage referred to the contrary. In µCT analysis, superior morphology could not be made in reference to increased or decreased bone density as this is currently unknown for the SCB specifically and therefore, the term was avoided in reference to bone density.

Results

BMS Group versus Untreated Group

The BMS group versus untreated group studies are presented in Table 3 .

Table 3.

BMS Group versus Untreated Group Studies.

Investigators	Year	Animal Species	No. of Animals	No. of CLs	CL Location(s)	No. of Holes for BMS	Diameter(s) of Holes for BMS (mm)	Depth(s) of Holes for BMS (mm)	Time(s) Until Evaluation	QoE (Modified Horn Scale)
Frisbie et al.¹⁶	1999	Horses	10	40	Femoral condyle; radial carpal bone	N/A	N/A	3.0	4 mo, 12 mo	3
Qiu et al.¹⁷	2003	Rabbits	33	33	Femoral condyle	1	3.0	3.0	8 w, 16 wk, 32 wk	3
Årøen et al.¹⁸	2006	Rabbits	41	82	Patella	4	N/A	3.0	1 wk, 2 wk, 36 wk	4
Frisbie et al.¹⁹	2006	Horses	12	48	Femoral condyle	N/A	N/A	3.0	4 mo, 12 mo	4
Hayashi et al.²⁰	2009	Rabbits	30	60	Tibial tuberosity	1	0.5	N/A	1 wk, 2 wk, 4 wk, 6 wk, 8 wk, 12 wk	2
Chen et al.²¹	2011	Rabbits	16	32	Trochlea	4	N/A	2.0, 6.0	3 mo	5
Orth et al.²²	2012	Sheep	19	19	Femoral condyle	6	1.0	10.0	6 mo	2
Eldracher et al.²³	2014	Sheep	13	13	Trochlea	6	1.0, 1.8	10.0	6 mo	5
Fisher et al.²⁴	2015	Pigs	11	22	Trochlea	3	4.0	2.0	6 wk	3
Orth et al.²⁵	2016	Sheep	24	24	Femoral condyle	6	1.0, 1.2	5.0	6 mo	5
Summary (n = 10)	1999 to 2006	Horses; rabbits; sheep; pigs	209 animals (total)	373 CLs (total)	Femoral condyle; radial carpal bone; patella; tibial tuberosity; trochlea	1-6 holes	1.0-4.0 mm	2.0-10.0 mm	1 wk to 12 mo	3.5 (average QoE)

BMS, bone marrow stimulation; CL, chondral lesion; QoE, quality of evidence.

Deep SCB

µCT assessment of the deep SCB included 5studies ( Table 4 ). A subacute phase study by Fisher et al.²⁴ indicated in both µCT and histology that neither the BMS or untreated group restored the bone density or histological architecture of the deep SCB back to normal (P < 0.05). Bone density comparisons between the BMS and untreated group revealed conflicting findings in the subacute phase. Chen et al.²¹ indicated significantly increased bone density in the untreated group compared with the BMS group whereas Fisher et al.²⁴ indicated the opposite of these findings. However, 3 late phase studies further supported the findings of Chen et al.²¹ indicating significantly increased bone densities in the untreated group than the BMS group (P < 0.05).^22,23,25

Table 4.

BMS Group versus Untreated Group Summary of Results.

Structure	Total No. of Studies	Acute Phase Studies (0 to 2 wk)	Subacute Phase Studies (2 wk to 3 mo)	Late Phase Studies (≥6 m)	No. of Animals	No. of CLs	No. of Holes for BMS	Diameter of Holes for BMS (mm)	Depth of Holes for BMS (mm)	Summary of Results
Deep SCB
µCT (BV/TV)	5^21 -25	0	2^21,24	3^22,23,25	83	110	4-6	1.0-4.0	2.0-10.0	Normal > untreated > BMS
Histology	1²⁴	0	1²⁴	0	11	22	3	4.0	2.0	Normal > BMS > untreated
Superficial SCB
µCT (BS/BV)Histology	4^21 -23,25	0	1²¹	3^22,23,25	72	88	4-6	1.0-1.8	2.0 to 10.0	BMS > untreated
Histology	9^16 -21,23-25	2^18,20	4^17,20,21,24	6^16-19,23,25	190	354	1-6	1.0-4.0	2.0-10.0	Normal > BMS > untreated
Cartilage
Histology	7^{16,18-20,23-25}	2^18,20	2^20,24	5^{16,18,19,23,25}	141	289	1-6	1.0-4.0	2.0-10.0	Normal > BMS > untreated

BMS, bone marrow stimulation; BS/BV, bone surface area over bone volume (mm⁻¹); BV/TV, bone volume over total volume (%); CL, chondral lesion; SCB, subchondral bone; µCT, microcomputed tomography.

Histological assessment of the deep SCB included 1 study in the subacute phase ( Table 4 ).²⁴ Inferior histological architectures were noted in both the BMS and untreated groups compared with normal. Additionally, superior histological architecture was indicated in the BMS group compared with the untreated group.

Superficial SCB

µCT assessment of the superficial SCB included 4 studies ( Table 4 ). µCT assessments did not compare either the BMS or untreated group to normal.^21-23,25 However, all studies indicated significantly increased bone densities in the BMS group compared with the untreated group (P < 0.05).

Histological assessment of the superficial SCB included 9 studies ( Table 4 ). In 6 studies that were collectively included in all time phases, inferior histological architectures were indicated in both the BMS and untreated groups compared with normal.^{17,19-21,23,24} Four studies that were also collectively included in all time phases indicated superior histological architectures in the BMS group compared with the untreated group.^16,18,24,25 Both µCT and histological assessments of the superficial SCB were similar, except for the lack of comparison to normal by µCT in both the BMS and untreated groups. Interestingly, Qiu et al.¹⁷ using drilling demonstrated in the only study of an osteochondral model (n = 33; osteochondral lesions = 33) that the superficial SCB had in fact overgrown beyond its native tidemark.

Cartilage

Histological assessment of the cartilage included 7 studies ( Table 4 ). In 5 studies that were collectively involved in all the time phases, inferior histological architectures were noted in both the BMS and untreated group compared with normal.^18-20,23,24 Three studies compared histological architectures between the BMS and untreated group in the acute and late phases revealed that the BMS group was significantly superior to the untreated group (P < 0.05).^16,18,25 However, a subacute phase study by Fisher et al.²⁴ instead indicated similar histological architecture between the BMS and untreated group.

Relationship Between Morphology of SCB and Cartilage Repair

Six studies of all time phases compared the morphological relationship of the SCB and cartilage in the BMS to untreated groups; increased bone density and superior histology of the superficial SCB was indicated to be related with increased hyaline-like cartilage repair.^{16,18-20,23,25} Two of these studies also assessed the deep SCB in the late phase, indicated that worsening morphology (specifically bone density) of the deep SCB related with increased hyaline-like cartilage repair.^23,25 However, 1 study conflicted both these findings in the subacute phase, indicating superior morphology of the deep SCB relating to increased hyaline-like cartilage repair and that there was no morphological relationship between the superficial SCB and hyaline-like cartilage repair.²⁴

BMS Group versus BMS-A Group

The BMS group versus BMS-A group studies are presented in Table 5 .

Table 5.

BMS Group versus BMS-A Group Studies.

Investigators	Year	Animal Species	No. of Animals	No. of CLs	CL Location(s)	No. of Holes for BMS	Diameter(s) of Holes for BMS (mm)	Depth(s) of Holes for BMS (mm)	Adjuvant(s)	Time(s) Until Evaluation	QoE (Modified Horn Scale)
Breinan et al.²⁷	2000	Dogs	12	12	Trochlea	2	0.8	1.5-2.0	Collagen matrix; autologous chondrocytes	15 wk	2
Dorotka et al.²⁸	2005	Sheep	11	22	Femoral condyle	2	4.5	N/A	Collagen matrix; autologous chondrocytes	16 wk	2
Dorotka et al.²⁹	2005	Sheep	27	54	Femoral condyle	2	4.5	N/A	Collagen matrix; autologous chondrocytes	4 mo, 12 mo	4
Hoemann et al.²⁶	2007	Rabbits	19	38	Trochlea	4	0.9	3.0-4.0	Chitosan matrix	8 wk	3
Hoemann et al.³⁰	2010	Rabbits	15	30	Trochlea	4	0.9	3.5	Chitosan matrix	1 wk, 2 wk, 8 wk	3
Bell et al.³¹	2012	Sheep	5	10	Femoral condyle	6	2.0	2.5-6.5	Chitosan matrix	1 d, 3 wk, 3 mo	5
Guzmán-Morales et al.³²	2014	Rabbits	7	14	Patella	2	1.5	2.0	Chitosan matrix	70 d	5
Summary (n = 7)	2000 to 2014	Dogs; sheep; rabbits	96 animals (total)	180 CLs (total)	Trochlea; femoral condyle; patella	2-6	0.8-4.5	1.5-6.5	Collagen matrix; autologous chondrocytes; chitosan matrix	1 d to 12 mo	3.0 (average QoE)

BMS, bone marrow stimulation; CL, chondral lesion; QoE, quality of evidence.

Deep SCB

µCT assessment of the deep SCB included 1 study in the subacute phase using chitosan matrix as the adjuvant.²⁶ µCT assessments did not compare either the BMS or BMS-A groups with normal. However, significantly increased bone density was indicated in the BMS-A group compared with the BMS group (P < 0.0005). Histological assessment of the deep SCB was not made in this study.

Superficial SCB

µCT assessment of the superficial SCB also included 1 study in the subacute phase using chitosan matrix as the adjuvant.²⁶ Similarly, no µCT assessments compared either the BMS or BMS-A groups to normal but significantly increased bone density was indicated in the BMS-A group compared with the BMS group (P < 0.0005).

Histological assessment of the superficial SCB included all 7 studies of this category ( Table 6 ). In all 7 studies that were collectively included in all time phases, no histological assessments in relation to normal for either the BMS or BMS-A groups were made.^26-32 Histological assessments made between the BMS and BMS-A groups revealed contrasting results depending on the adjuvant used. Four studies in the acute and subacute phases using chitosan matrix adjuvants indicated superior histological architecture in the BMS-A group compared with the BMS group.^26,30-32 A range of results was presented when collagen matrix and autologous chondrocytes adjuvants was compared with the BMS group. Breinan et al.²⁷ indicated superior histological architecture in both the collagen matrix and autologous chondrocytes groups compared with the BMS group. However, 2 other studies by the same first author (Dorotka),^28,29 compared collagen matrix and autologous chondrocytes adjuvants to the BMS group alone at 4 months revealed inferior histological architecture in the collagen matrix adjuvant but superior histological architecture in the autologous chondrocytes adjuvant. However, one of these studies also evaluated the outcomes at 12 months and indicated superior histology in both the collagen matrix and the autologous chondrocytes groups at that time point.²⁹

Table 6.

BMS Group versus BMS-A Group Summary of Results.

Structure	Total No. of Studies	Acute Phase Studies (0-2 wk)	Subacute Phase Studies (2 wk to 3 mo)	Late Phase Studies (≥6 mo)	No. of Animals	No. of CLs	No. of Holes for BMS	Diameter of Holes for BMS (mm)	Depth of Holes for BMS (mm)	Summary of Results
Deep SCB
µCT (BV/TV)	1²⁶	0	1²⁶	0	19	38	4	0.9	3.0-4.0	BMS-A (chitosan matrix) > BMS
Superficial SCB
µCT (BS/BV)	1²⁶	0	1²⁶	0	19	38	4	0.9	3.0-4.0	BMS-A (chitosan matrix) > BMS
Histology	7^26-32	2^30,31	4^26,30-32	1²⁹	96	180	2-6	0.8-4.5	1.5-6.5	BMS-A > BMS
Cartilage
Histology	7^26-32	2^30,31	4^26,30-32	1²⁹	96	180	2-6	0.8-4.5	1.5-6.5	BMS-A > BMS

BMS, bone marrow stimulation; BMS-A, bone marrow stimulation + adjuvant; BS/BV, bone surface area over bone volume (mm⁻¹); BV/TV, bone volume over total volume (%); CL, chondral lesion; SCB, subchondral bone; µCT, microcomputed tomography.

Cartilage

Histological assessment of the cartilage also included all 7 studies of this category ( Table 6 ). The findings here were similar to that of the histological assessment of the superficial SCB except in the study by Breinan et al.,²⁷ where similar results were revealed in both the collagen matrix and the autologous chondrocyte groups compared with the BMS group. However, this result was statistically insignificant in the study.

Relationship Between Morphology of SCB and Cartilage Repair

Seven studies of all time phases compared the morphological relationship of the SCB and cartilage in the BMS and BMS-A groups indicated that increased bone density and superior histology of the SCB related with increased hyaline-like cartilage repair. This was observed in 4 studies of all time phases assessing the morphology of the superficial SCB^28-32 and 1 study assessing the morphology of both the superficial and deep SCB.²⁶ One study revealed a lack of relationship between the morphology of the superficial SCB and hyaline-like cartilage repair.²⁶

Discussion

The consensus of postoperative morphological status of SCB following BMS and its impact on cartilage repair and clinical outcomes has not been established yet, despite the advocates of the important role of the SCB in cartilage repair.¹² This systematic review demonstrated that contemporary BMS techniques resulted in alterations of the SCB in preclinical animal models. Specifically, bone density of the deep SCB significantly decreased to the untreated defect. In addition, biological adjuvants appeared to improve the morphology of the SCB compared with BMS alone. Although no conclusive outcomes have not been achieved in available studies, increased bone density and superior histology of superficial SCB may be important for cartilage repair. In this systematic review, animal studies were different experimental designs including different BMS techniques, different animal species, different locations of defects in the joint (trochlea vs tibia vs condyles). The variations in articular cartilage and SCB biomechanics between joints should be carefully accounted for when interpreting these results.³³ Nevertheless, these outcomes may be valuable for further research because of the consistency of the findings among the studies.

Successful cartilage repair and re-loading at the defect site would be expected to increase bone density due to an innate plasticity of bone that allows it to adapt to shield greater forces in accordance with Wolff’s law.³⁴ However, this was not observed in the current study for the deep SCB; superficial SCB was not reported. Although the etiology of these findings is uncertain, a number of potential mechanisms may be responsible for this phenomenon and warrant consideration. At the tissue level, inferior biomechanical properties of fibrocartilage and loss of the calcified cartilage layer may alter force transduction and fluid flow within the defect and in the SCB below.³⁵ At the cellular level, mechanotransduction of bone cells (similar to chondrocytes) is mediated by primary cilia responding to load-mediated local shifts of interstitial fluid pressure.³⁶ It is currently unclear if penetration of SCB with exposure to the joint environment, loss of the calcified cartilage (and vascular watershed) and more permeable fibrocartilaginous repair tissue are capable of disrupting osteoblast mechanotransduction locally at the microfractured defect.

Given the importance of SCB in cartilage health,^7-11 the relationship between the affected SCB and cartilage repair tissue quality and quantity was important concern in this systematic review. Although no conclusive outcomes have not been achieved in current available studies, increased bone density and superior histology of superficial SCB may be important for cartilage repair.^{16,18-20,23,24} The current study also demonstrated that bone density of the deep SCB is significantly reduced in the BMS group when compared with the untreated group. These characterizations provide a basis to investigate less detrimental approaches to improve the quality and quantity of the reparative fibrocartilage. In accordance, Gianakos et al.¹² reported superior SCB morphology for 1.0 mm diameter awls compared with the 2.0 mm in the talar cadaver model. Eldracher et al.²³ reported superior cartilage repair and SCB morphology for 1.0-mm diameter drilling compared with 1.8 mm at 6 months in the sheep trochlear defect model. Orth et al.²⁵ also reported superior cartilage repair and SCB morphology but for 1.0 mm diameter awls compared with 1.2 mm at 6 months in the medial femoral condyle of the sheep model. While the smaller awl resulted in reduced morphological disruption of the SCB, SCB cysts and intralesional osteophytes were observed at similar frequencies. In contrast, Marchland et al.³⁷ compared 0.5- and 0.9-mm diameter drill holes in the rabbit model observed no difference in the cartilage tissue repair or SCB morphology at 6 months. Kok et al.³⁸ similarly observed no difference between 0.45- and 1.1-mm diameter awls in the talar osteochondral defects of a goat model. With regard to the relationship between morphology of deep SCB and quality and quantity of reparative cartilage tissue, the current study showed the conflict findings.^23-25 Despite these findings, as similar to superficial SCB, deep SCB is supposed to be important structure for cartilage repair, based on the function of SCB for the articular cartilage. Chen et al.³⁹ reported that 6-mm depth holes produced statistically superior cartilage repair compared with 2-mm depth holes at 3 months in the rabbit trochlear defect model. Further investigations should focus on the relationship between morphology of SCB and quality and quantity of reparative cartilage tissue as well as less impassive subchondral penetration approaches.

The optimal approach to improve the quality of cartilage repair is to enhance regeneration of the cartilage whilst also promoting the restoration of the SCB affected by BMS. Currently, various biologics have been used in cartilage repair, including platelet-rich plasma, concentrated bone marrow aspirate, scaffold-based therapy and chondrocyte-based therapy. Successful short-term functional outcomes following these biological adjuvant therapies in bone marrow stimulation have been reported.^6,40 However, little information remains available for their capabilities for the health of the SCB in BMS. Outcomes from the current systematic review suggest that biological adjuvants (collagen matrix, autologous chondrocytes and chitosan matrix) may improve the morphology of the SCB than that of BMS alone. Postulations can include innate osteochondroconductive and/or -inductive properties of the biological adjuvants. Future studies that incorporate both the morphology of the SCB and cartilage health as measures of BMS success are needed to confirm this finding.

Several inherent limitations could have hindered the accuracy of findings in this study. The QoE was assessed according to Modified Horn Scale whereby the validity remains questionable, as no studies have validated this scale to date. Secondly, the translation of the findings from animal to human models remains a challenge as the potential differ in joint loading and innate structural stability in animals can mislead the understanding in humans. Finally, the marked heterogeneity from the vast range of animals, surgical techniques and outcome measures exhausted may affect the clinical translation of the results. Nevertheless, as these findings were consistent, the outcomes from current study is valuable for future studies investigating the SCB.

Conclusion

In this systematic review, animal studies were different experimental designs, including different BMS techniques, different animal species, different locations of defects in the joint (trochlea vs. tibia vs. condyles). Nevertheless, obtained outcomes were the consistency among the studies. The current study demonstrated that BMS techniques resulted in alterations of the SCB and that biological adjuvants appeared to improve the morphology of the SCB compared with BMS alone. Refinements of BMS techniques should incorporate consideration of SCB damage and restoration. Investigations to optimize BMS techniques incorporating both minimally invasive approaches and biologically augmented platforms are further warranted.

Footnotes

Acknowledgments and Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: John G. Kennedy is a consultant for Arteriocyte, Inc; received research support from the Ohnell Family Foundation, Mr. and Mrs. Michael J. Levitt, Arteriocyte Inc; is a board member for the European Society of Sports Traumatology, Knee Surgery, and Arthroscopy (ESSKA), International Society for Cartilage Repair of the Ankle (ISCRA), American Orthopaedic Foot & Ankle Society (AOFAS) Awards and Scholarships Committee, International Cartilage Repair Society (ICRS) finance board.

Ethics approval

Ethical approval was not sought for the present study because this study is a systematic review of published animal studies.

Animal welfare

Guidelines for humane animal treatment did not apply to the present study because this study is a systematic review of published animal studies.

References

Miller

Smith

Matava

Wright

Brophy

RH.

Microfracture and osteochondral autograft transplantation are cost-effective treatments for articular cartilage lesions of the distal femur. Am J Sports Med. 2015;43(9):2175-81. doi:10.1177/0363546515591261.

Mithoefer

McAdams

Scopp

Mandelbaum

BR.

Emerging options for treatment of articular cartilage injury in the athlete. Clin Sports Med. 2009;28(1):25-40. doi:10.1016/j.csm.2008.09.001.

Murawski

Kennedy

JG.

Operative treatment of osteochondral lesions of the talus. J Bone Joint Surg Am. 2013;95(11):1045-54. doi:10.2106/JBJS.L.00773.

Mithoefer

McAdams

Williams

Kreuz

Mandelbaum

BR.

Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am J Sports Med. 2009;37(10):2053-63. doi:10.1177/0363546508328414.

Zengerink

Struijs

Tol

van Dijk

CN.

Treatment of osteochondral lesions of the talus: a systematic review. Knee Surg Sports Traumatol Arthrosc. 2010;18(2):238-46. doi:10.1007/s00167-009-0942-6

Yasui

Wollstein

Murawski

Kennedy

JG.

Operative treatment for osteochondral lesions of the talus: biologics and scaffold-based therapy. Cartilage. 2016. doi:10.1177/1947603516644298

Madry

van Dijk

Mueller-Gerbl

The basic science of the subchondral bone. Knee Surg Sports Traumatol Arthrosc. 2010;18(4):419-33. doi:10.1007/s00167-010-1054-z.

Brown

Vrahas

MS.

The apparent elastic modulus of the juxtarticular subchondral bone of the femoral head. J Orthop Res. 1984;2(1):32-8.

Duncan

Jundt

Riddle

Pitchford

Christopherson

The tibial subchondral plate. A scanning electron microscopic study. J Bone Joint Surg Am. 1987;69(8):1212-20.

10.

Pan

Wang

Zhou

Scherr

Yang

. Elevated cross-talk between subchondral bone and cartilage in osteoarthritic joints. Bone. 2012;51(2):212–217. doi:10.1016/j.bone.2011.11.030.

11.

Goldring

SR.

Alterations in periarticular bone and cross talk between subchondral bone and articular cartilage in osteoarthritis. Ther Adv Musculoskel Dis. 2012;4(4):249-58. doi:10.1177/1759720X12437353.

12.

Gianakos

Yasui

Fraser

Ross

Prado

Fortier

. The effect of different bone marrow stimulation techniques on human talar subchondral bone: a micro-computed tomography evaluation. arthroscopy. 2016;32(10):2110-7. doi:10.1016/j.arthro.2016.03.028.

13.

Liberati

Altman

Tetzlaff

Mulrow

Gøtzsche

Ioannidis

. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W65-94.

14.

Horn

de Haan

Vermeulen

Luiten

Limburg

Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke. 2001;32(10):2433-8.

15.

Yeom

Blanchard

Kim

Zunt

Chu

TM.

Correlation between micro-computed tomography and histomorphometry for assessment of new bone formation in a calvarial experimental model. J Craniofac Surg. 2008;19(2):446-52. doi:10.1097/SCS.0b013e318052fe05.

16.

Frisbie

Trotter

Powers

Rodkey

Steadman

Howard

. Arthroscopic subchondral bone plate microfracture technique augments healing of large chondral defects in the radial carpal bone and medial femoral condyle of horses. Vet Surg. 1999;28(4):242-55.

17.

Qiu

Shahgaldi

Revell

Heatley

FW.

Observations of subchondral plate advancement during osteochondral repair: a histomorphometric and mechanical study in the rabbit femoral condyle. Osteoarthritis Cartilage. 2003;11(11):810-20.

18.

Arøen

Heir

Løken

Engebretsen

Reinholt

FP.

Healing of articular cartilage defects. An experimental study of vascular and minimal vascular microenvironment. J Orthop Res. 2006;24(5):1069-77.

19.

Frisbie

Morisset

Rodkey

Steadman

McIlwraith

CW.

Effects of calcified cartilage on healing of chondral defects treated with microfracture in horses. Am J Sports Med. 2006;34(11):1824-31.

20.

Hayashi

Kumai

Higashiyama

Shinohara

Matsuda

Takakura

Repair process after fibrocartilaginous enthesis drilling: histological study in a rabbit model. J Orthop Sci. 2009;14(1):76-84. doi:10.1007/s00776-008-1284-9.

21.

Chen

Chevrier

Hoemann

Sun

Ouyang

Buschmann

MD.

Characterization of subchondral bone repair for marrow-stimulated chondral defects and its relationship to articular cartilage resurfacing. Am J Sports Med. 2011;39(8):1731-40. doi:10.1177/0363546511403282.

22.

Orth

Goebel

Wolfram

Ong

Gräber

Kohn

. Effect of subchondral drilling on the microarchitecture of subchondral bone: analysis in a large animal model at 6 months. Am J Sports Med. 2012;40(4):828-36. doi:10.1177/0363546511430376.

23.

Eldracher

Orth

Cucchiarini

Pape

Madry

Small subchondral drill holes improve marrow stimulation of articular cartilage defects. Am J Sports Med. 2014;42(11):2741-50. doi:10.1177/0363546514547029.

24.

Fisher

Belkin

Milby

Henning

Bostrom

Kim

. Cartilage repair and subchondral bone remodeling in response to focal lesions in a mini-pig model: implications for tissue engineering. Tissue Eng Part A. 2015;21(3-4):850-60. doi:10.1089/ten.TEA.2014.0384.

25.

Orth

Duffner

Zurakowski

Cucchiarini

Madry

Small-diameter awls improve articular cartilage repair after microfracture treatment in a translational animal model. Am J Sports Med. 2016;44(1):209-19. doi:10.1177/0363546515610507.

26.

Hoemann

Sun

McKee

Chevrier

Rossomacha

Rivard

. Chitosan-glycerol phosphate/blood implants elicit hyaline cartilage repair integrated with porous subchondral bone in microdrilled rabbit defects. Osteoarthritis Cartilage. 2007;15(1):78-89.

27.

Breinan

Martin

Hsu

Spector

Healing of canine articular cartilage defects treated with microfracture, a type-II collagen matrix, or cultured autologous chondrocytes. J Orthop Res. 2000;18(5):781-9.

28.

Dorotka

Windberger

Macfelda

Bindreiter

Toma

Nehrer

Repair of articular cartilage defects treated by microfracture and a three-dimensional collagen matrix. Biomaterials. 2005;26(17):3617-29.

29.

Dorotka

Bindreiter

Macfelda

Windberger

Nehrer

Marrow stimulation and chondrocyte transplantation using a collagen matrix for cartilage repair. Osteoarthritis Cartilage. 2005;13(8):655-64.

30.

Hoemann

Chen

Marchand

Tran-Khanh

Thibault

Chevrier

. Scaffold-guided subchondral bone repair: implication of neutrophils and alternatively activated arginase-1+ macrophages. Am J Sports Med. 2010;38(9):1845-56. doi:10.1177/0363546510369547.

31.

Bell

Lascau-Coman

Sun

Chen

Lowerison

Hurtig

. Bone-induced chondroinduction in sheep Jamshidi biopsy defects with and without treatment by subchondral chitosan-blood implant: 1-day, 3-week and 3-month repair. Cartilage. 2012;4(2):131-143. doi:10.1177/1947603512463227.

32.

Guzmán-Morales

Lafantaisie-Favreau

Chen

Hoemann

CD.

Subchondral chitosan/blood implant-guided bone plate resorption and woven bone repair is coupled to hyaline cartilage regeneration from microdrill holes in aged rabbit knees. Osteoarthritis Cartilage. 2014;22(2):323-33. doi:10.1016/j.joca.2013.12.011.

33.

Chevrier

Kouao

Picard

Hurtig

Buschmann

MD.

Interspecies comparison of subchondral bone properties important for cartilage repair. J Orthop Res. 2015;33(1):63-70. doi:10.1002/jor.22740.

34.

Frost

HM.

A 2003 update of bone physiology and Wolff’s law for clinicians. Angle Orthod. 2004;74(1):3-15.

35.

Mow

Mak

Lai

Rosenberg

Tang

LH.

Viscoelastic properties of proteoglycan subunits and aggregates in varying solution concentrations. J Biomech. 1984;17(5):325-38.

36.

Malone

Anderson

Tummala

Kwon

Johnston

Stearns

. Primary cilia mediate mechanosensing in bone cells by a calcium-independent mechanism. Proc Natl Acad Sci U S A. 2007;104(33):13325-30.

37.

Marchand

Chen

Tran-Khanh

Sun

Chen

Buschmann

. Microdrilled cartilage defects treated with thrombin solidified chitosan/blood implant regenerate a more hyaline, stable, and structurally integrated osteochondral unit compared to drilled controls. Tissue Eng Part A. 2012;18(5-6):508-519. doi:10.1089/ten.TEA.2011.0178.

38.

Kok

Tuijthof

den Dunnen

van Tiel

Siebelt

Everts

. No effect of hole geometry in microfracture for talar osteochondral defects. Clin Orthop Relat Res. 2013;471(11):3653-62. doi:10.1007/s11999-013-3189-y.

39.

Chen

Hoemann

Sun

Chevrier

McKee

Shive

. Depth of subchondral perforation influences the outcome of bone marrow stimulation cartilage repair. J Orthop Res. 2011;29(8):1178-84. doi:10.1002/jor.21386.

40.

Smyth

Murawski

Haleem

Hannon

Savage-Elliott

Kennedy

JG.

Establishing proof of concept: platelet-rich plasma and bone marrow aspirate concentrate may improve cartilage repair following surgical treatment for osteochondral lesions of the talus. World J Orthop. 2012;3(7):101-8. doi:10.5312/wjo.v3.i7.101.

The Subchondral Bone Is Affected by Bone Marrow Stimulation: A Systematic Review of Preclinical Animal Studies

Abstract

Objective

Design

Results

Conclusions

Keywords

Introduction

Methods

Search Strategy

Data Evaluation

SCB and Cartilage Assessment

Definition of Morphology

Results

BMS Group versus Untreated Group

Deep SCB

Superficial SCB

Cartilage

Relationship Between Morphology of SCB and Cartilage Repair

BMS Group versus BMS-A Group

Deep SCB

Superficial SCB

Cartilage

Relationship Between Morphology of SCB and Cartilage Repair

Discussion

Conclusion

Footnotes

Acknowledgments and Funding

Declaration of Conflicting Interests

Ethics approval

Animal welfare

References