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Orthopaedic Proceedings
Vol. 87-B, Issue SUPP_III | Pages 348 - 348
1 Sep 2005
Laurencin C Cooper J Sahota J Gorum J Carter J Ko F Doty S
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Introduction and Aims: There are more than 200,000 anterior cruciate ligament (ACL) ruptures each year in the United States. The replacements used for ACL repair do not fully recreate the ACL’s function and histological appearance. Therefore, a novel tissue-engineered ligament was designed and evaluated after ACL reconstruction in a rabbit model.

Method: Rabbits received tissue-engineered ligaments or tissue-engineered ligaments seeded with primary rabbit ACL cells. The tissue-engineered ligaments were composed of multifilament poly-L-lactide yarn (70 denier) fabricated into novel 24 yarn 3-D braids. Scaffolds were designed to be easily handled and fixed by the surgeon in ACL reconstructions using the suture over the button technique. A continuous scaffold design accommodated the flexibility of intra-articular loads and the rigours of the bone tunnels. The contralateral legs were used as controls. A key parameter for tissue ingrowth was scaffold porosity at 58 ± 9% and mode pore diameter of 183 ± 83 μm.

Results: Histological evaluations showed slow collagen tissue infiltration at the surface of the replacement at the four-week time point for both the tissue-engineered ligament and cell-seeded tissue-engineered ligament. At the 12-week time point, both replacements showed collagen ingrowth and remodelling across the entire implant occurred with a thin fibrous capsule. The cell-seeded tissue-engineered ligament demonstrated greater levels of mature collagen ingrowth and healing compared to the non-cell seeded tissue-engineered ligament. The initial tensile strength properties of the scaffold were 332 ± 20 N and 354 ± 68 MPa, which compared well to the rabbit ACL control (314 ± 66 N). The tensile properties of the tissue-engineered ligament and seeded tissue-engineered ligament at four weeks were 67% and 76%, respectively of control. The tensile properties of the biodegradable implant decreased with time for the tissue-engineered and cell seeded tissue-engineered ligament and by 12 weeks was 9% and 30% respectively, as compared to the rabbit ACL control. The 30% strength retention for the tissue-engineered ligament replacements at 12 weeks was greater than reported by others using poly(lactic acid) and polypropylene ligament augmentation devices (LAD) at 12 weeks, with values of 13% and 16% of control strength retention, respectively.

Conclusion: The results of this study demonstrate the promise of a novel cell seeded tissue-engineered ligament for anterior cruciate ligament regeneration.


Orthopaedic Proceedings
Vol. 86-B, Issue SUPP_I | Pages 93 - 93
1 Jan 2004
Diwan AD Khan SN Peterkin M Cammisa FP Sandhu HS Doty S Lane JM
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Nitric oxide (NO) is a free radical labile gas which has important physiological functions and is synthesised by the action of a group of enzymes called nitric oxide synthases (NOS) on L- arginine. We have shown that nitric oxide modulates fracture healing1. Bone morphogenic proteins (BMP) are potent differentiating factors that augment the process of new bone formation. Recombinant human BMP-2 (rhBMP-2) enhances spinal fusion2. With progression of fusion there is a remodelling of the fusion mass bone accompanied with a decrease in the fusion mass size. It is not known whether nitric oxide has a role in spinal fusion or rhBMP-2 enhanced spinal fusion.

We studied this in a novel rat intertransverse fusion model using a defined volume of bone graft (7 caudal vertebrae) along with 157 mm3 of absorbable Type-1 collagen sponge (Helistat®) carrier, which was compacted and delivered using a custom jig for achieving a similar graft density from sample to sample. The control groups consisted of a sham operated group (S, n=20), an autograft + carrier group (AC, n=28) and a group consisting of 43μg of rhBMP-2 (Genetics Institute, Andover, MA) mixed with autograft + carrier (ACB, n=28). Two experimental groups received a nitric oxide syn-thase (NOS) inhibitor, NG-nitro L-arginine methyl ester (L-NAME, Sigma Chemicals, St Louis, MO) in a dose of 1mg/ml ad lib in the drinking water (ACL, n=28) and one of these experimental groups had rhBMP-2 added to the graft mixture at the time of surgery (ACLB, n=28). Rats were sacrificed at 22 days and 44 days, spinal columns dissected and subjected to high density radiology (faxitron) and decalcified histology. The faxitrons were subjected to image analysis (MetaMorph).

On a radiographic score (0–4) indicating progressive maturation of bone fusion mass, no difference was found between the AC and ACL groups, however, there was a significant enhancement of fusion when rhBMP-2 was added (ACB group,3.3±0.2) when compared to the AC group (1±0) (p< .001). However, on day 44, the ACLB group (3.3±0.2) showed significantly less fusion progression when compared to the ACB group (4±0) (p< 0.01). There was a 25% (p< 0.05) more fusion-mass-area in day 44 of ACLB group (297±26 mm3) when compared to day 44 of the ACB group (225±16 mm3) indicating that NOS inhibition delayed the remodelling of the fusion mass. Undecalcified histology demonstrated that there was a delay in graft incorporation whenever NOS was inhibited (ACL and ACLB groups).

Our results show that the biology of autograft spinal fusion and rhBMP-2 enhanced spinal fusion can be potentially manipulated by nitric oxide pathways.


Orthopaedic Proceedings
Vol. 85-B, Issue SUPP_III | Pages 288 - 289
1 Mar 2003
Diwan A Khan S Peterkin M Cammisa F Sandhu H Doty S Lane J
Full Access

Nitric oxide (NO) is a free radical labile gas which has important physiological functions and is synthesised by the action of a group of enzymes called nitric oxide synthases (NOS) on L- arginine. We have shown that nitric oxide modulates fracture healing1. Bone morphogenic proteins (BMP) are potent differentiating factors that augment the process of new bone formation. Recombinant human BMP-2 (rhBMP-2) enhances spinal fusion2. With progression of fusion there is a remodelling of the fusion mass bone accompanied with a decrease in the fusion mass size. It is not known whether nitric oxide has a role in spinal fusion or rhBMP-2 enhanced spinal fusion.

We studied this in a novel rat intertransverse fusion model using a defined volume of bone graft (7 caudal vertebrae) along with 157 mm3 of absorbable Type-1 collagen sponge (Helistat®) carrier, which was compacted and delivered using a custom jig for achieving a similar graft density from sample to sample. The control groups consisted of a sham operated group (S, n=20), an autograft + carrier group (AC, n=28) and a group consisting of 43 μg of rhBMP-2 (Genetics Institute, Andover, MA) mixed with autograft + carrier (ACB, n=28). Two experimental groups received a nitric oxide synthase (NOS) inhibitor, NG-nitro L-arginine methyl ester (L-NAME, Sigma Chemicals, St Louis, MO) in a dose of 1 mg/ml ad lib in the drinking water (ACL, n=28) and one of these experimental groups had rhBMP-2 added to the graft mixture at the time of surgery (ACLB, n=28). Rats were sacrificed at 22 days and 44 days, spinal columns dissected and subjected to high density radiology (faxitron) and decalcified histology. The faxitrons were subjected to image analysis (MetaMorph).

On a radiographic score (0–4) indicating progressive maturation of bone fusion mass, no difference was found between the AC and ACL groups, however, there was a significant enhancement of fusion when rhBMP-2 was added (ACB group, 3.3±0.2) when compared to the AC group (1±0) (p< .001). However, on day 44, the ACLB group (3.3±0.2) showed significantly less fusion progression when compared to the ACB group (4±0) (p< 0.01). There was a 25% (p< 0.05) more fusion-mass-area in day 44 of ACLB group (297±26 mm3) when compared to day 44 of the ACB group (225±16 mm3) indicating that NOS inhibition delayed the remodelling of the fusion mass. Undecalcified histology demonstrated that there was a delay in graft incorporation whenever NOS was inhibited (ACL and ACLB groups).

Our results show that the biology of autograft spinal fusion and rhBMP-2 enhanced spinal fusion can be potentially manipulated by nitric oxide pathways.


The Journal of Bone & Joint Surgery British Volume
Vol. 74-B, Issue 3 | Pages 380 - 384
1 May 1992
Lee J Salvati E Betts F DiCarlo E Doty S Bullough P

Reports of differing failure rates of total hip prostheses made of various metals prompted us to measure the size of metallic and polyethylene particulate debris around failed cemented arthroplasties. We used an isolation method, in which metallic debris was extracted from the tissues, and a non-isolation method of routine preparation for light and electron microscopy. Specimens were taken from 30 cases in which the femoral component was of titanium alloy (10), cobalt-chrome alloy (10), or stainless steel (10). The mean size of metallic particles with the isolation method was 0.8 to 1.0 microns by 1.5 to 1.8 microns. The non-isolation method gave a significantly smaller mean size of 0.3 to 0.4 microns by 0.6 to 0.7 microns. For each technique the particle sizes of the three metals were similar. The mean size of polyethylene particles was 2 to 4 microns by 8 to 13 microns. They were larger in tissue retrieved from failed titanium-alloy implants than from cobalt-chrome and stainless-steel implants. Our results suggest that factors other than the size of the metal particles, such as the constituents of the alloy, and the amount and speed of generation of debris, may be more important in the failure of hip replacements.