LEXINGTON, KY, United States
LEXINGTON, KY, United States
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Zhu K.,Orthopeutics, Lp | Hedman T.,Orthopeutics, Lp | Hedman T.,Texas A&M University
Natural Product Communications | Year: 2010

Degradation of genipin (GP), a low toxicity natural protein crosslinking agent, in aqueous solution was monitored by HPLC at various pH levels. Degradation of GP was consistent with a mechanism consisting of a first order reaction with a reversible first step. Formation of the intermediate was slowest at more neutral pHs while formation of the irreversible product was correlated to increasing alkalinity. Degradation at all pHs was enhanced by the presence of phosphate ions. Degradation of GP most likely proceeds via the reversible opening of the dihydropyran ring by water followed by irreversible polymerization of the intermediate. Degraded solutions containing no detectable GP or intermediate, however, are still capable of crosslinking proteins.


Slusarewicz P.,Orthopeutics, Lp | Zhu K.,Orthopeutics, Lp | Kirking B.,Orthopeutics, Lp | Kirking B.,Texas A&M University | And 3 more authors.
Spine | Year: 2011

Study Design. Biochemical studies aimed at optimization of protein crosslinking formulations for the treatment of degenerative disc disease and subsequent biomechanical testing of tissues treated with these formulations. Objective. To optimize protein crosslinking formulations for treatment of degenerating spinal discs. Summary of Background Data. Nonsurgical exogenous crosslinking therapy is a potential new, noninvasive technology for the treatment of degenerative disc disease. The technology is based on the injection of protein crosslinking reagents into the pathologic disc to restore its mechanical properties and also to potentially increase the permeability of the tissue and so facilitate the exchange of waste products and nutrients. Methods. Diffusion of genipin (GP) was monitored following injection into spinal discs and the effects of surfactants on diffusion studied. Formulations for GP and methylglyoxal (MG) were biochemically optimized and used to treat bovine spinal discs. Their effects on bovine anulus tissue were evaluated using a circumferential tensile test, while the GP formulation was also tested with respect to its ability to reduce disc bulge under load. Results. GP exhibited a distinct time-dependent diffusion and sodium-dodecyl-sulfate, but not Tween-20, enhanced diffusion by 30%. Two crosslinkers, GP and MG, were inhibited by amines but enhanced by phosphate ions. Both formulations could enhance a number of physical parameters of bovine anulus tissue, while the GP formulation could reduce disc bulge following injections into spinal discs. Conclusion. Formulations lacking amines and containing phosphate ions appear to be promising candidates for clinical use of the crosslinkers GP and MG. Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


Slusarewicz P.,Orthopeutics, Lp | Zhu K.,Orthopeutics, Lp | Hedman T.,Orthopeutics, Lp | Hedman T.,Texas A&M University
Journal of Materials Science: Materials in Medicine | Year: 2010

We have characterized the relative efficacies of a number of protein crosslinking agents that have the potential for use in the crosslinking of proteinaceous matrices both in vitro and in vivo. The crosslinkers tested were; l-threose (LT), Genipin (GP), Methylglyoxal (MG), 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC), proanthrocyanidin (PA) and glutaraldehyde (GA). The relative effectiveness of the crosslinkers with regard to their saturating concentrations was: GA > PA > EDC > MG = GP ≫ LT. Most of the crosslinkers displayed a pH dependence and were more effective at more alkaline pH. At optimal pH and saturating conditions, the relative reaction rates of the crosslinkers were: PA = GA > EDC > GP > MG ≫ LT. © 2010 Springer Science+Business Media, LLC.


Zhu K.,Orthopeutics, Lp | Slusarewicz P.,Orthopeutics, Lp | Hedman T.,Orthopeutics, Lp | Hedman T.,Texas A&M University
Journal of Orthopaedic Research | Year: 2011

Treatment of a pathological spinal disc in vivo by injection of protein crosslinking reagents to restore the disc's mechanical properties is a new approach to the treatment of degenerative disc disease. In this study, the thermal stability of the collagen in disc annulus was measured by differential scanning calorimetry following treatment with six different crosslinking agents. The crosslinkers used were; L-threose (LT), genipin (GP), methylglyoxal (MG), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), glutaraldehyde (GA), and proanthrocyanidin (PA). Untreated tissue displayed a prominent peak at about 66-68°C. Comparison of endothermal patterns of untreated and crosslinker-treated disc annulus tissue samples showed that a new peak appeared at a higher temperature following treatment. The temperature of the new peak qualitatively depended on the crosslinker in the following order GAa>aMGa>aGPa>aPA=EDCa>aLT, suggesting that the enhanced thermal stability of collagen in the annulus tissue was related to the nature of the crosslinker. Also, the enthalpic ratios of the lower temperature (noncrosslinked) peaks in the treated and untreated tissue, and of the higher and lower temperature peaks in the treated tissue, both indicated that the various agents crosslinked the tissue with different efficiencies. Our data suggest that the ability of GP to penetrate into the disc and form long- and short-range crosslinks may make it the most suitable candidate for clinical development. In addition, binary combinations of long- and short-range crosslinkers, such as PA with LT, may also provide synergistic effects due to their substantially different physicochemical properties. © 2011 Orthopaedic Research Society.


Patent
Orthopeutics, Lp | Date: 2015-04-13

A method of treating a tear in a knee meniscus of a patient. The method includes exposing the torn knee meniscus to a protein crosslinker during surgery to repair the tear. Also provided is a fixation device for the surgical repair of tears of the meniscus of the knee, where the device contains one or more protein crosslinking reagents.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 767.90K | Year: 2010

DESCRIPTION (provided by applicant): With regard to prevalence and cost to society, low-back pain has few peers. With a patient population in excess of 15 million/year, the societal cost is estimated to be in the realm of 100 billion/year. Current treatment options for this disease have shown limited success, including physical therapy, medication and surgery. This proposal involves a novel, nonsurgical and cost-effective, tissue revitalization approach which shows promise for treatment of mechanically and nutritionally challenged tissues like the spinal disc. Previous in vitro and in vivo studies have demonstrated the efficacy of Injectable collagen crosslink augmentation in stabilizing spinal joints, decreasing disc bulge under load, increasing the strength, tear resistance, and durability of the tissue, while also improving nutritional flow to these largely avascular tissues. Phase I testing was successful in characterizing the crosslinking effects of seven candidate agents in disc annulus fibrosis (AF) tissue using mechanical, thermal and protease digestion assays. At least one preferred agent was identified, and concentration, pH, conditioning, and buffering were optimized to maximize the efficiency of crosslinking and mechanical effect. Recently, in vitro assays have been undertaken to determine agent and buffer biocompatibility. The proposed Phase II testing will provide data necessary for regulatory filings and first-in-man clinical trials. Reagent delivery, penetration, reaction kinetics, permanency (effect duration), and storage requirements (shelf life) will be thoroughly investigated. Acute, functional biocompatibility and neurotoxicity studies will be conducted to quantify expected and worst-case treatment effects in an animal model. Further characterization of crosslinking effects will be determined using different subgroups of human AF tissues (variations in age, composition, degeneration). By bringing this path-breaking treatment to the doorstep of clinical trials, SBIR funding will play a vital role in enabling progress towards the ultimate goal of providing a novel, cost-effective treatment in the struggle against low back pain and disability. PUBLIC HEALTH RELEVANCE: Back pain and disability associated with spinal degeneration and instability remains among the most costly and prevalent health problems in the US today. With a patient population in excess of 15 million/year, the societal cost is estimated to be in the realm of 100 billion/year. Due to the limited success of current treatment options, it is reasonable to expect that an effective nonsurgical solution could revolutionize clinical care for this pandemic.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 244.90K | Year: 2013

DESCRIPTION (provided by applicant): Snoring is a condition that affects people of all ages, with a reported prevalence of up to 48% of men and 34% of women. Snoring poses not only an inconvenience with regard to sleep-cycle disruption of the sufferer's bed partner and family, but it can also lead to sleep-deprivation in the sufferer and to a more serious and sometimes life-threatening condition, obstructive sleep apnea syndrome (OSAS), where breathing is interrupted during sleep by physical obstruction ofthe airway. Prevalence of OSAS in the United States has been estimated at 4.2% for those aged 16 and older, or approximately 10 million individuals. Both snoring and OSAS are in most cases the result of obstructed airflow due to abnormalities in the geometry of the air passages and the propensity for aberrant deformation of the soft palate. Repeated trauma to the soft palate due to snoring can be expected to increase its passive deformability and damage muscle fibers and peripheral nerve fibers, increasingthe tendency for obstruction. Thus, treatment of snoring can play an important role in reducing the incidence of OSAS. Current treatments include surgery, the use of oral appliances, and more recently, minimally invasive procedures targeted at stiffeningthe soft palate. All of the newer procedures rely to some extent on the formation of fibrotic scar tissue to stiffen the soft palate. This fibrotic tissue can be expected to exhibit inferior mechanical properties and loss of structural integrity, leadingto the eventual loss of some initial treatment-related benefits. This Phase I study aims to determine feasibility of injecting non-toxic protein crosslinking agents to stiffen the soft palate without producing scar tissue. Previous testing suggests that this technique can augment the soft palate's mechanical properties, reduce vibration, and concomitantly increase resistance to mechanical degradation. The overall aim of this program will be to commercialize a less expensive, faster (same-day benefit), andsuperior injectable treatment for the reduction of snoring, prevention of OSAS, and reduction of airway collapse. Feasibility will be evaluated in four parts: 1) the ability of crosslinking agents to improve the mechanical properties and increase the resistance to mechanical degradation of soft palate tissue will be tested; 2) a wind tunnel test system will be developed to measure the vibration magnitude and oscillation frequency of horse soft palates; 3) the wind tunnel will be used to quantify reduction of vibration in horse soft palates following preferred crosslinker injections; ad 4) safety and treatment effect will be evaluated in pilot studies involving treatment of soft palats in normal horses and horses diagnosed with dorsal displacement of the softpalate (DDSP) which involves a form of awake snoring and apnea. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Snoring is a highly prevalent condition that can lead to sleep-deprivation in the sufferer and to a more serious and sometimes life-threatening condition, obstructive sleep apnea syndrome (OSAS), where breathing is interrupted during sleep by physical obstruction of the airway. Current treatments for snoring and OSAS include surgery, the use of oral appliances, and more recently, minimally invasive procedures directed at stiffening the soft palate, all of which rely on the formation of mechanically inferior scar tissue We propose to investigate a less expensive injectable agent which we believe, based on previous studies, can improve thesoft palate's mechanical properties, reduce vibration, and concomitantly increase resistance to mechanical degradation, for the reduction of snoring, prevention of OSAS, and reduction of airway collapse.


Patent
Orthopeutics, Lp | Date: 2014-02-12

A protein crosslinker delivery device includes a body and a protein crosslinker held in a synthetic or natural biodegradable polymer. The body, a coating on the body, or an attachment to the body can contain the protein crosslinker holding biodegradable polymer. The release rate of the crosslinker and total amount of crosslinker released can be controlled by varying the concentration of the crosslinker and by varying the composition and structural characteristics of the degradable polymer. Surface eroding, bulk eroding and naturally occurring biodegradable polymers can be used in conjunction with a variety of nontoxic or minimally-toxic protein crosslinking agents. The devices can be used to treat mechanically damaged, deformed, and nutritionally deficient connective or soft tissues such as the knee meniscus, the spinal disc, the cornea, ligaments and tendons, the soft palate, and skin.


Patent
Orthopeutics, Lp | Date: 2011-05-26

A method of treating a tear in a knee meniscus of a patient. The method includes exposing the torn knee meniscus to a protein crosslinker during surgery to repair the tear. Also provided is a fixation device for the surgical repair of tears of the meniscus of the knee, where the device contains one or more protein crosslinking reagents.


A method of treating snoring and/or OSA in a subject in need of such treatment. The method includes crosslinking proteins of the subjects soft palate tissue or pharynx tissue. The crosslinking can occur by contacting the soft palate or pharynx tissue with a crosslinking reagent. In addition, the crosslinking can occur without heating, contracting or denaturing of the tissue, or any combination thereof.

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