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BMP-2 and BMP-2/7 Heterodimers Conjugated to a Fibrin/Hyaluronic Acid Hydrogel in a Large Animal Model of Mild Intervertebral Disc Degeneration.

Peeters M, Detiger SE, Karfeld-Sulzer LS, Smit TH, Yayon A, Weber FE, Helder MN - Biores Open Access (2015)

Bottom Line: All animals maintained weight throughout the study and no heterotopic bone formation or other adverse effects were noted during follow-up.MRI T2* mapping showed strong and significant correlations with biochemistry and histology as shown before.The conjugated BMP-2 and BMP-2/7 appeared safe, but no disc regeneration was observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, VU University Medical Center , Amsterdam, The Netherlands . ; Center for Translational Regenerative Medicine (CTRM), MOVE Research Institute Amsterdam , Amsterdam, The Netherlands .

ABSTRACT
Intervertebral disc (IVD) degeneration is etiologically associated with low back pain and is currently only treated in severe cases with spinal fusion. Regenerative medicine attempts to restore degenerated tissue by means of cells, hydrogels, and/or growth factors and can therefore be used to slow, halt, or reverse the degeneration of the IVD in a minimally invasive manner. Previously, the growth factors bone morphogenetic proteins 2 and 7 (BMP-2, -7) were shown to enhance disc regeneration, in vitro and in vivo. Since BMPs have only a short in vivo half-life, and to prevent heterotopic ossification, we evaluated the use of a slow release system for BMP-2 homodimers and BMP-2/7 heterodimers for IVD regeneration. BMP growth factors were conjugated to a fibrin/hyaluronic acid (FB/HA) hydrogel and intradiscally injected in a goat model of mild IVD degeneration to study safety and efficacy. Mild degeneration was induced in five lumbar discs of seven adult Dutch milk goats, by injections with the enzyme chondroitinase ABC. After 12 weeks, discs were treated with either FB/HA-hydrogel only or supplemented with 1 or 5 μg/mL of BMP-2 or BMP-2/7. BMPs were linked to the FB/HA hydrogels using a transglutaminase moiety, to be released through an incorporated plasmin cleavage site. After another 12 weeks, goats were sacrificed and discs were assessed using radiography, MRI T2* mapping, and biochemical and histological analyses. All animals maintained weight throughout the study and no heterotopic bone formation or other adverse effects were noted during follow-up. Radiographs showed significant disc height loss upon induction of mild degeneration. MRI T2* mapping showed strong and significant correlations with biochemistry and histology as shown before. Surprisingly, no differences could be demonstrated in any parameter between intervention groups. To our knowledge, this is the first large animal study evaluating BMPs conjugated to an FB/HA-hydrogel for the treatment of mild IVD degeneration. The conjugated BMP-2 and BMP-2/7 appeared safe, but no disc regeneration was observed. Possible explanations include too low dosages, short follow-up time, and/or insufficient release of the conjugated BMPs. These aspects should be addressed in future studies.

No MeSH data available.


Related in: MedlinePlus

Scatter plots and linear regression lines indicating correlations between MRI T2* relaxation times (msec) and (a) glycosaminoglycan (GAG) content (μg/mg dry weight) (ρ = 0.76, p < 0.0001), (b) collagen (HYP) content (μg/mg dry weight) (ρ = −0.61, p < 0.0001), and (c) histological grade (range 0–6) (ρ = −0.53, p = 0.0002). ρ, Spearman's rho correlation coefficient; R2, linear regression coefficient.
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f2: Scatter plots and linear regression lines indicating correlations between MRI T2* relaxation times (msec) and (a) glycosaminoglycan (GAG) content (μg/mg dry weight) (ρ = 0.76, p < 0.0001), (b) collagen (HYP) content (μg/mg dry weight) (ρ = −0.61, p < 0.0001), and (c) histological grade (range 0–6) (ρ = −0.53, p = 0.0002). ρ, Spearman's rho correlation coefficient; R2, linear regression coefficient.

Mentions: Figure 2 shows the scatter plots and correlations between the MRI T2* relaxation times in the NP and the amount of GAG, collagen content (HYP), and histological grading. We found a strong correlation between the T2* relaxation times and the amount of GAGs for the NP (ρ = 0.76, p < 0.0001). Moderate, yet highly significant, correlations were observed between T2* relaxation times of the NP and the collagen content (ρ = −0.61, p < 0.0001) and histological grading (ρ = −0.53, p = 0.0002). Concerning the inner and outer annulus fibrosus, only weak and no significant correlations were found for T2* relaxation times and other outcome parameters.


BMP-2 and BMP-2/7 Heterodimers Conjugated to a Fibrin/Hyaluronic Acid Hydrogel in a Large Animal Model of Mild Intervertebral Disc Degeneration.

Peeters M, Detiger SE, Karfeld-Sulzer LS, Smit TH, Yayon A, Weber FE, Helder MN - Biores Open Access (2015)

Scatter plots and linear regression lines indicating correlations between MRI T2* relaxation times (msec) and (a) glycosaminoglycan (GAG) content (μg/mg dry weight) (ρ = 0.76, p < 0.0001), (b) collagen (HYP) content (μg/mg dry weight) (ρ = −0.61, p < 0.0001), and (c) histological grade (range 0–6) (ρ = −0.53, p = 0.0002). ρ, Spearman's rho correlation coefficient; R2, linear regression coefficient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4623986&req=5

f2: Scatter plots and linear regression lines indicating correlations between MRI T2* relaxation times (msec) and (a) glycosaminoglycan (GAG) content (μg/mg dry weight) (ρ = 0.76, p < 0.0001), (b) collagen (HYP) content (μg/mg dry weight) (ρ = −0.61, p < 0.0001), and (c) histological grade (range 0–6) (ρ = −0.53, p = 0.0002). ρ, Spearman's rho correlation coefficient; R2, linear regression coefficient.
Mentions: Figure 2 shows the scatter plots and correlations between the MRI T2* relaxation times in the NP and the amount of GAG, collagen content (HYP), and histological grading. We found a strong correlation between the T2* relaxation times and the amount of GAGs for the NP (ρ = 0.76, p < 0.0001). Moderate, yet highly significant, correlations were observed between T2* relaxation times of the NP and the collagen content (ρ = −0.61, p < 0.0001) and histological grading (ρ = −0.53, p = 0.0002). Concerning the inner and outer annulus fibrosus, only weak and no significant correlations were found for T2* relaxation times and other outcome parameters.

Bottom Line: All animals maintained weight throughout the study and no heterotopic bone formation or other adverse effects were noted during follow-up.MRI T2* mapping showed strong and significant correlations with biochemistry and histology as shown before.The conjugated BMP-2 and BMP-2/7 appeared safe, but no disc regeneration was observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, VU University Medical Center , Amsterdam, The Netherlands . ; Center for Translational Regenerative Medicine (CTRM), MOVE Research Institute Amsterdam , Amsterdam, The Netherlands .

ABSTRACT
Intervertebral disc (IVD) degeneration is etiologically associated with low back pain and is currently only treated in severe cases with spinal fusion. Regenerative medicine attempts to restore degenerated tissue by means of cells, hydrogels, and/or growth factors and can therefore be used to slow, halt, or reverse the degeneration of the IVD in a minimally invasive manner. Previously, the growth factors bone morphogenetic proteins 2 and 7 (BMP-2, -7) were shown to enhance disc regeneration, in vitro and in vivo. Since BMPs have only a short in vivo half-life, and to prevent heterotopic ossification, we evaluated the use of a slow release system for BMP-2 homodimers and BMP-2/7 heterodimers for IVD regeneration. BMP growth factors were conjugated to a fibrin/hyaluronic acid (FB/HA) hydrogel and intradiscally injected in a goat model of mild IVD degeneration to study safety and efficacy. Mild degeneration was induced in five lumbar discs of seven adult Dutch milk goats, by injections with the enzyme chondroitinase ABC. After 12 weeks, discs were treated with either FB/HA-hydrogel only or supplemented with 1 or 5 μg/mL of BMP-2 or BMP-2/7. BMPs were linked to the FB/HA hydrogels using a transglutaminase moiety, to be released through an incorporated plasmin cleavage site. After another 12 weeks, goats were sacrificed and discs were assessed using radiography, MRI T2* mapping, and biochemical and histological analyses. All animals maintained weight throughout the study and no heterotopic bone formation or other adverse effects were noted during follow-up. Radiographs showed significant disc height loss upon induction of mild degeneration. MRI T2* mapping showed strong and significant correlations with biochemistry and histology as shown before. Surprisingly, no differences could be demonstrated in any parameter between intervention groups. To our knowledge, this is the first large animal study evaluating BMPs conjugated to an FB/HA-hydrogel for the treatment of mild IVD degeneration. The conjugated BMP-2 and BMP-2/7 appeared safe, but no disc regeneration was observed. Possible explanations include too low dosages, short follow-up time, and/or insufficient release of the conjugated BMPs. These aspects should be addressed in future studies.

No MeSH data available.


Related in: MedlinePlus