Maximizing distribution and minimizing washout of injectates in bone and method for enhanced aspirate extraction
The present invention provides methods of distributing agents into bone and the maintenance of those agents within bone. These methods include mechanical, rheological, pharmacological, and other methods. By maintaining injectates within a targeted location in bone and increasing their distribution in bone, the methods are useful for purposes including but not limited to increasing local concentration, improving therapeutic effectiveness, increasing duration of action, and decreasing systemic toxicity. These same methods can displace the contents of bone toward a harvesting instrument for purposes of collection with similar and complimentary methods. The methods are useful for controlling the rate of egress of intraosseous distribution of agents or cells for a variety of purposes, including but not limited to: augmenting stem cell recovery in bone marrow aspiration, chemotherapy, medication delivery, treatment of infection, bone augmentation, and the like.
1 . A method of modulating a rate of egress and intraosseous distribution of a first injectate, comprising steps of:
providing a volume of the first injectate comprising at least one therapeutic agent;
injecting the volume of the first injectate into a first region of an intramedullary bone site;
providing a volume of a second injectate comprising at least one vasoactive agent;
injecting the volume of the second injectate into a second region of the intramedullary bone site, wherein the first and second regions are different regions; and
maintaining the volume of the first injectate within the intramedullary bone site in a localized state such that between 15% to 95% of the volume of the first injectate is retained for between 5 minutes to 2 hours.
2 . The method of claim 1 , wherein the step of providing the volume of the first injectate is preceded by a step of providing a volume of a preliminary injectate at a pressure selected from the group consisting of about: 10 psi, 20 psi, 30 psi, 40 psi, 50 psi, 60 psi, 70 psi, 80 psi, 90 psi, 100 psi, 200 psi, 300 psi, 400 psi, 500 psi, 600 psi, 700 psi, 800 psi, 900 psi, and 1000 psi, wherein connections between surrounding venules at the intramedullary bone site are opened by way of incomplete or fragile sinusoidal walls.
3 . The method of claim 1 , wherein the step of providing the volume of the first injectate is preceded by a step of providing a volume of a preliminary injectate at a rate-selected from the group consisting of about: 0.1 μL/s, 1 μL/s, 10 μL/s, 50 μL/s, 0.1 mL/s, 0.2 mL/s, 0.3 mL/s, 0.4 mL/s, 0.5 mL/s, 0.6 mL/s, 0.7 mL/s, 0.8 mL/s, 0.9 mL/s, 1 mL/s, 2 mL/s, 3 mL/s, 4 mL/s, 5 mL/s, 6 mL/s, 7 mL/s, 8 mL/s, 9 mL/s, and 10 mL/s, wherein connections between surrounding venules at the intramedullary bone site are opened by way of incomplete or fragile sinusoidal walls.
4 . The method of claim 1 , wherein the at least one vasoactive agent is a vasoconstrictive agent selected from the group consisting of: a sympathomimetic, methoxamine hydrochloride, epinephrine, dobutamine, dopamine, norepinephrine, milrinone, midodrine hydrochloride, desglymidodrine, and an alphareceptor agonist, stimulant or activator.
5 . The method of claim 1 , wherein the at least one vasoactive agent is a vasodilative agent selected from the group consisting of: alpha or beta adrenergic receptor modulators, muscarine, histamine, dopamine receptor modulators, an organic nitrate, isosorbide mononitrate, a mononitrate, isosorbide dinitrate, a dinitrate, nitroglycerin, a trinitrate, minoxidil, sodium nitroprusside, hydralazine hydrochloride, nitric oxide, nicardipine hydrochloride, fenoldopam mesylate, diazoxide, enalaprilat, epoprostenol sodium, a prostaglandin, milrinone lactate, a bipyridine, and a dopamine D1-like receptor agonist, stimulant or activator.
6 . The method of claim 1 , wherein the at least one therapeutic agent is selected from the group consisting of: an anti-tumor agent, an antiproliferative agent, an anti-angiogenic agent, a cytotoxic agent, an antimicrobial (including anti-bacterial and anti-fungal) agent, a cell mobilizing agent, and a pain-relieving agent.
7 . The method of claim 1 , further comprising a step of extracting a volume of aspirate from one or more additional regions of the intramedullary bone site after the step of maintaining the volume of the first injectate within the intramedullary bone site in the localized state, such that a pressure gradient is formed across a vasculature or a bone field between the intramedullary bone site having a first pressure and the one or more additional regions of the intramedullary bone site each having a pressure lower than the first pressure.
8 . The method of claim 7 , wherein the one or more additional regions of the intramedullary bone site are each between about 5 mm to about 500 mm distant from the first region of the intramedullary bone site.
9 . The method of claim 7 , wherein the step of injecting the volume of the first injectate and the step of extracting are performed at sequential depths at the first region of the intramedullary bone site and the one or more additional regions of the intramedullary bone site, respectively.