NOTE AMENDMENT AND RELEASE OF COLLATERAL

Exhibit 4.1

NOTE AMENDMENT AND RELEASE OF COLLATERAL

This Note Amendment and Release of Collateral is made as of this 20th day of July, 2009 by and among Cardium Therapeutics, Inc., a Delaware corporation (the “Company”), and holders (each a “Holder”) of a senior subordinated secured promissory notes issued pursuant to the terms of that certain Note and Warrant Purchase Agreement dated February 27, 2009 (“Purchase Agreement”). Capitalized terms used but not defined herein shall have the meanings ascribed to such terms in the Notes.

W I T N E S S E T H

WHEREAS, the Company issued and sold an aggregate principal amount of $3,500,000 of senior subordinated secured promissory notes pursuant to the Purchase Agreement, of which an aggregate principal amount of $2,550,000 of such notes are dated February 27, 2009 and an aggregate principal amount of $950,000 of such notes are dated March 5, 2009, and each of which were amended by certain Amendments to Promissory Notes dated as of June 23, 2009 and July 10, 2009 by and among the Company and the Holders (such senior subordinated secured promissory notes as amended are referred to herein as the “Notes”);

WHEREAS, pursuant to the terms of a Security Agreement dated as of February 27, 2009 (the “Security Agreement”), by and among the holders of the Notes, the Company, InnerCool Therapies, Inc., a Delaware corporation and wholly-owned subsidiary of the Company (“InnerCool”), Tissue Repair Company, a Delaware corporation and wholly-owned subsidiary of the Company, and Dr. Robert Marshall as collateral agent (the “Collateral Agent”) payment of the Notes is secured by, among other things, a lien on the assets of InnerCool (the “InnerCool Assets”);

WHEREAS, on July 10, 2009, the Company and InnerCool entered into an Asset Purchase Agreement (the “Philips APA”) with Philips Electronics North America Corporation, a Delaware corporation (“Philips”), pursuant to which Philips will purchase substantially all of the InnerCool Assets (the “Philips Transaction”), and the Company and Holders wish to facilitate the consummation of the Philips Transaction, pursuant to which the InnerCool Assets are to be acquired by Philips free and clear of any liens created by the Security Agreement or otherwise;

WHEREAS, certain Holders of the Notes wish to take advantage of an offer by the Company to extend the term of all or a portion of their Note as set forth in Section 2 below (the “Optional Term Extension”) in exchange for the receipt of the following payments (collectively the “Term Extension Payments”):

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NOW, THEREFORE, for good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the parties hereto hereby agree as follows:

1. Acknowledgement and Note Extension. Holder acknowledges that each holder of Notes is being afforded an opportunity to individually elect to extend the maturity of such holder’s Note to November 5, 2009 and to otherwise modify and amend such Note as set forth in Section 2 below. In addition, Holder and the Company agree that, effective as of the date hereof, all of the Notes shall be amended as follows:

1.1 Section 3 of each Note is hereby amended to read in its entirety as follows:

3. Maturity. Unless sooner paid in accordance with the terms hereof, the entire unpaid principal amount and all unpaid accrued interest shall become fully due and payable on the earlier of (i) July 23, 2009, or (ii) the acceleration of the maturity of this Note by the Holder upon the occurrence of an Event of Default (such earlier date, the “Maturity Date”).

1.2 Section 5(a)(i) of each Note is hereby amended to delete the words “twenty-three (23) days” and in place thereof insert the words “two (2) Business Days” so that Section 5(a)(i) of the Note shall read in its entirety as follows:

(i) any indebtedness under this Note is not paid when and as the same shall become due and payable, whether at maturity, by acceleration, thirty-five (35) days following notice of prepayment or otherwise, and any such amount shall remain unpaid for a period of two (2) Business Days after the due date thereof

2. Optional Term Extension; Term Extension Payments.

Please indicate below whether you wish to have this Section 2 apply to your Note in exchange for which you will be entitled to receive the Optional Term Extension Payments (including the First Payment, Monthly Payments and Final Pay-Off Amount as described above), with respect to that portion of your Note that you elect to extend (minimum amount for extension 50%).

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2.1 Note Extension and Amendments. The Company and the undersigned holder agree that, subject to payment of the First Payment, the Note shall be amended as follows:

(a) Section 3 of the Note shall be amended to read in its entirety as follows:

3. Maturity. Unless sooner paid in accordance with the terms hereof, the entire unpaid principal amount and all unpaid accrued interest shall become fully due and payable on the earlier of (i) November 5, 2009, or (ii) the acceleration of the maturity of this Note by the Holder upon the occurrence of an Event of Default (such earlier date, the “Maturity Date”).

(b) Section 4(b) of the Note shall be amended to read in its entirety as follows:

(b) Interest Payments. The Company shall pay to Holder accrued interest and unpaid interest on the last Business Day of each month commencing with July 31, 2009 and on the Maturity Date. Interest at the rate first set forth above shall accrue on any interest which has not been paid on the date on which it is payable until such time as payment therefor is actually delivered to Holder.

(c) Section 4(c) of the Note shall be deleted in its entirety.

2.2 Release of Collateral. The Holder hereby consents to the transactions contemplated by the Philips APA and waives any violation or default of Transaction Documents (as defined in the Purchase Agreement) that might otherwise arise by reason thereof. In connection therewith, upon satisfaction of the Effectiveness Conditions, Holder approves, and hereby directs the Collateral Agent to effectuate, the release of any and all liens on the Collateral (as defined in the Security Agreement) to be conveyed to Philips pursuant to the Philips APA.

2.3 Timing. The parties hereto contemplate that the amounts payable as part of the Effectiveness Conditions shall be paid at the closing of the transactions contemplated by the Philips APA. To remove any doubt arising from the order in which transactions may take place, the parties hereto agree that any transactions contemplated hereby and by the Philips APA, if occurring on the same day, shall be deemed to have occurred simultaneously.

3. Execution in Counterparts. This Note Amendment and Release of Collateral may be executed in any number of counterparts, each of which when so executed and delivered shall be deemed an original, and such counterparts together shall constitute one instrument. Delivery by facsimile or other electronic means of an executed counterpart hereof shall have the same force and effect as delivery of an originally executed counterpart hereof.

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IN WITNESS WHEREOF, the undersigned, by their duly authorized representatives, have executed this Note Amendment and Release of Collateral as of the date first above written.

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