**6. Clinical relevance of alginate-based biomaterials**

#### **6.1 Type 1 diabetes mellitus treatment**

While extensively performed in animal models for several decades, islet xenotransplantations have taken more time in advancing to clinical human

**47**

be tested clinically in the future.

Alginate has shown effectiveness as a constituent of acellular matrix skin grafts to reduce wound healing duration, which is especially poor with diabetic patients

**6.2 Wound healing treatment**

*Current Perspective and Advancements of Alginate-Based Transplantation Technologies*

studies around the world. This is because the area of xenografts in general is still a highly regulated area in the transplantation field and is being studied heavily in animal models [118, 119]. In the United States, the stringent FDA regulations for all xenotransplantations has provided certain standards which must be achieved pre-clinically before moving to clinical trials [120]. This has made initiation of clinical trials involving alginate xenografts very slow in the United States. Nonetheless, here have recently been a small amount of clinical islet xenotransplantation trials that have been conducted outside of the US using porcine islet xenografts to treat IDDM in human subjects (**Table 1**). The first phase I/IIa clinical trial saw 7 T1DM patients receive up to 3 implantations of encapsulated neonatal porcine islets which resulted in 5 patients with improved blood glucose levels and two patients which achieved insulin independence for up to 32 weeks post-transplantation [121, 122]. From 2000 to 2003 in a clinical trial in Mexico, two cohorts totaling 21 IDDM patients underwent xenograft implantation of a collagen-covered pre-vascularized scaffold which housed 250,000 islets with 30,000–100,000 Sertoli cells. After the first transplantation HbA1C showed significant reductions, with decreases in exogenous insulin demands observed for up to 4 years, and glucose stimulated C-peptide detected in urine for up to 4 years; in addition, zoonotic transmission of porcine microorganisms was not detected for the duration of the study [123–125]. Unfortunately, the human clinical trial in Mexico did not include a control population under exogenous insulin therapy that could further validate the results [121]. In patients who received a steroid-based regimen 33–62% decrease in insulin requirements for up to 1 year with detectable presence of porcine C-peptide compared to two patients, which received steroid-free regimen, who saw change in IDDM conditions [126]. A comprehensive 2011 study, 14 IDDM patients were given 5000–20,000 IE/kg intraperitoneally via laparoscopy using wildtype pre-weaned juvenile porcine islets without immunosuppressive therapy for 52 weeks [127]. Overall, 8 of the 14 patients showed a moderate decrease in insulin administration and HbA1C levels. A nonsignificant reduction in severe hypoglycemic events, or unaware hypoglycemic episodes, was also observed in the same patients [127, 128]. Alginate-based macrodevices have been the topic of heavy research since the late 1940s and recently have been tested clinically as a scaffold for therapeutic islet-delivery [115]. Patients with T1D have been subcutaneously implanted with macroencapsulated, bioartificial pancreatic βAir (BetaO2 Technologies Ltd., Israel) device; the study designed to monitor for 180 days post-transplantation followed by removal of the device, and 6 months of follow-up afterwards. The device involved oxygen pumps which allowed for daily refueling of oxygen to devices while in-vivo. For the duration of the study, islets in the device did not face any immune rejection and survived to time of explant. Although there were no rejections in the body, the overall efficacy of the islets was low and metabolic control was absent; C-peptide levels were detected on day 1 of post-transplantation in all patients (range 0.028–0.093 nmol/L) and remained detectable up until 2–4 weeks but for one patient detectable up to 3 months post-transplantation [129, 130]. Continued research into alginate immune-isolation of pancreatic islet xenografts will continue to develop and will

*DOI: http://dx.doi.org/10.5772/intechopen.87120*

#### *Current Perspective and Advancements of Alginate-Based Transplantation Technologies DOI: http://dx.doi.org/10.5772/intechopen.87120*

studies around the world. This is because the area of xenografts in general is still a highly regulated area in the transplantation field and is being studied heavily in animal models [118, 119]. In the United States, the stringent FDA regulations for all xenotransplantations has provided certain standards which must be achieved pre-clinically before moving to clinical trials [120]. This has made initiation of clinical trials involving alginate xenografts very slow in the United States. Nonetheless, here have recently been a small amount of clinical islet xenotransplantation trials that have been conducted outside of the US using porcine islet xenografts to treat IDDM in human subjects (**Table 1**). The first phase I/IIa clinical trial saw 7 T1DM patients receive up to 3 implantations of encapsulated neonatal porcine islets which resulted in 5 patients with improved blood glucose levels and two patients which achieved insulin independence for up to 32 weeks post-transplantation [121, 122]. From 2000 to 2003 in a clinical trial in Mexico, two cohorts totaling 21 IDDM patients underwent xenograft implantation of a collagen-covered pre-vascularized scaffold which housed 250,000 islets with 30,000–100,000 Sertoli cells. After the first transplantation HbA1C showed significant reductions, with decreases in exogenous insulin demands observed for up to 4 years, and glucose stimulated C-peptide detected in urine for up to 4 years; in addition, zoonotic transmission of porcine microorganisms was not detected for the duration of the study [123–125]. Unfortunately, the human clinical trial in Mexico did not include a control population under exogenous insulin therapy that could further validate the results [121]. In patients who received a steroid-based regimen 33–62% decrease in insulin requirements for up to 1 year with detectable presence of porcine C-peptide compared to two patients, which received steroid-free regimen, who saw change in IDDM conditions [126]. A comprehensive 2011 study, 14 IDDM patients were given 5000–20,000 IE/kg intraperitoneally via laparoscopy using wildtype pre-weaned juvenile porcine islets without immunosuppressive therapy for 52 weeks [127]. Overall, 8 of the 14 patients showed a moderate decrease in insulin administration and HbA1C levels. A nonsignificant reduction in severe hypoglycemic events, or unaware hypoglycemic episodes, was also observed in the same patients [127, 128]. Alginate-based macrodevices have been the topic of heavy research since the late 1940s and recently have been tested clinically as a scaffold for therapeutic islet-delivery [115]. Patients with T1D have been subcutaneously implanted with macroencapsulated, bioartificial pancreatic βAir (BetaO2 Technologies Ltd., Israel) device; the study designed to monitor for 180 days post-transplantation followed by removal of the device, and 6 months of follow-up afterwards. The device involved oxygen pumps which allowed for daily refueling of oxygen to devices while in-vivo. For the duration of the study, islets in the device did not face any immune rejection and survived to time of explant. Although there were no rejections in the body, the overall efficacy of the islets was low and metabolic control was absent; C-peptide levels were detected on day 1 of post-transplantation in all patients (range 0.028–0.093 nmol/L) and remained detectable up until 2–4 weeks but for one patient detectable up to 3 months post-transplantation [129, 130]. Continued research into alginate immune-isolation of pancreatic islet xenografts will continue to develop and will be tested clinically in the future.

#### **6.2 Wound healing treatment**

Alginate has shown effectiveness as a constituent of acellular matrix skin grafts to reduce wound healing duration, which is especially poor with diabetic patients

*Alginates - Recent Uses of This Natural Polymer*

assisted by T lymphocytes [100]. Both macrophages and lymphocytes secrete inflammatory mediators. Examples of these include cytokines IL-1β, IL-6, and TNFα and chemokines IL-8, MCP, MIP-1β, and ENA-78, all of which are known to activate and recruit inflammatory effector cells such as neutrophils, monocytes, T lymphocytes, and natural killer cells [100, 105]. Similarly, it was discovered that certain cytokine, chemokine levels, matrix metalloproteinases (MMPs) and tissue inhibitor MMPs (TIMP), fluctuated over time which suggests that T lymphocyte-macrophage interactions have the ability to facilitate the chronic inflammatory phase of the FBR [100, 108]. There have been *in vivo* studies that have shown active T cells in response to synthetic materials during an inflammatory response; however, *in vitro* studies have shown a lack of lymphocyte response to alginate biomaterials [100, 109]. A novel focus of study regarding mitogens, which are functional groups on the surface of biomaterials, led to the hypothesis that they can possibly trigger lymphocytes via cross-linking of glycoproteins, but these mitogenic properties have not been observed [100]. The chronic inflammatory period usually subsides 2 weeks after implantation and any longer periods of inflammation are usually the result of infection [100, 102]. A combination of granulation, fibroblast infiltration, and macrophage/fibroblast surface adhesion

result in the final fibrotic encapsulation of alginate biomaterials.

**6. Clinical relevance of alginate-based biomaterials**

While extensively performed in animal models for several decades, islet xenotransplantations have taken more time in advancing to clinical human

**6.1 Type 1 diabetes mellitus treatment**

To overcome the challenges of inflammation and fibrosis associated with the foreign body response after alginate hydrogels are implanted, researchers are currently trying to establish technologies for potential immune modulation. Research into alginate immune-modulation methods currently involves the use of bioactive nanoparticles, immune regulatory cells, hydrogel surface topography, and passive non-fouling agents [110]. In the past bioactive nanoparticles, like ketoprofen, have shown potential to modulate the degree of inflammation during FBR [111]. A recent study was able to load monoclonal antibody IgM nanoparticles during alginate encapsulation of pancreatic islets. This resulted in localized controlled release of the monoclonal antibody after implantation which decreased the immune response against transplants [112]. An islet transplantation study using the anti-inflammatory nanoparticle rapamycin, demonstrated reduced fibrosis and sustained glycemic control improvement [113]. Mesenchymal-derived stem cells have been shown to have a wide range of regenerative effects on several tissue injury types because of their multipotent capacity [114]. Several recent studies have demonstrated immune modulation of alginate hydrogels through co-delivery of MSCs with cell-delivery systems. This can help reduces inflammation and can modulate T-cell toxicity while also boosting wound healing properties and blood vessel formation of the graft site [115–117]. A better understanding of the mechanism of FBR in the future will help improve immune modulation technologies for transplantations involving

**5.3 Immuno-modulation of alginate hydrogels**

**46**

alginate hydrogels.


#### **Table 1.**

*Selected clinical encapsulated islet xenotransplantations in humans. IE is used to denote islet equivalents that make up the graft which are implanted during transplantation.*

**49**

*Current Perspective and Advancements of Alginate-Based Transplantation Technologies*

[131–133]. A large multicenter study involving 75 patients with 100 wounds (50% UT grade 3 wounds) was conducted using an alginate containing GraftJacket® matrix skin graft. The study resulted in 91% of complete wound closure averaging around 9.6 weeks indicating the graft was a safe option for complex lower extremity wounds [134]. Recent clinical studies with an alginate containing skin graft known as AlloPatch® have shown the effectiveness in wound healing even when elevated HbA1C levels witnessed in one patient [135]. Several alginate-based skin grafts are commercially available for advanced wound healing which include Nu-Gel® (Systagenix), Tegagel® (3M GmbH)), Curasorb® Alginate (Medtronic), Sorbsan® (B. Braun Melsungen AG), and Kendall™ Hydrocolloid Dressing (Medtronic) [136]. Advances in the development of alginate matrices will continue to contribute

The hydrophilic nature of alginate along with hydrogel forming and biocompatible nature has made it a staple hydrocolloid for application in the field of dentistry [137]. Alginate-based gels have traditionally been used in dentistry to provide the dentist with impressions of teeth and bitemarks which can then be used as a template for dental implants [138–140]. Alginate is frequently used in clinical trials to obtain impressions when comparing various dental procedures [141–144]. In a recent clinical trial, silicone was found to be favored among patients in terms of comfortability although alginate impressions were found to be a cheaper procedure option [145, 146]. Alginate-containing matrices have also been tested for advanced periodontitis treatment, when compared to the normal 0.2% chlorhexidine treatment alginate-containing Emdogain® saw significant reduction in plaque viability [147]. These alginate-containing enamel matrices have also shown significant clinical regenerative capabilities for periodontal disease symptoms such as intrabony

The development and use of alginate macro/micro devices for implantation have met both improvements and challenges. Specifically, alginate has been used in the production of microcapsules as well as scaffolds as a way to implant encapsulated islet cells in *vivo*. The use of natural polymers such as alginate introduces immunogenic and foreign body responses, which impact the functionality of the device over time [150]. For example, the mechanical integrity or structure of the device could be compromised, or it can decompose while inside the recipient. As a potential solution, alginate can be chemically modified so its properties can be better controlled against inflammatory response and mechanical stress [151]. This chemical modification includes both ionic and covalent crosslinks within alginate polymers which will increase the mechanical stability of both scaffolds and microcapsules [151]. This method of using two types of crosslinking to create the microbeads compared to using only covalent crosslinking has shown results of greater stability of these microcapsules within cells after weeks following implantation [151]. Furthermore, in the long run, purification techniques of alginate hydrogels can be improved to decrease PAMP concentration which would help reduce FBR [92]. Purifying alginate gels of PAMPs can be difficult for those with a high G content, which are stronger and more viscous. However, the use of chemical extraction or dialysis methods as well as specific purification methods would be required to remove these molecules. Another potential

*DOI: http://dx.doi.org/10.5772/intechopen.87120*

**6.3 Clinical uses in dentistry**

defects and gingival recession [148, 149].

**7. Future direction for alginate-based biotechnologies**

to skin regeneration therapy improvements in the future.

*Current Perspective and Advancements of Alginate-Based Transplantation Technologies DOI: http://dx.doi.org/10.5772/intechopen.87120*

[131–133]. A large multicenter study involving 75 patients with 100 wounds (50% UT grade 3 wounds) was conducted using an alginate containing GraftJacket® matrix skin graft. The study resulted in 91% of complete wound closure averaging around 9.6 weeks indicating the graft was a safe option for complex lower extremity wounds [134]. Recent clinical studies with an alginate containing skin graft known as AlloPatch® have shown the effectiveness in wound healing even when elevated HbA1C levels witnessed in one patient [135]. Several alginate-based skin grafts are commercially available for advanced wound healing which include Nu-Gel® (Systagenix), Tegagel® (3M GmbH)), Curasorb® Alginate (Medtronic), Sorbsan® (B. Braun Melsungen AG), and Kendall™ Hydrocolloid Dressing (Medtronic) [136]. Advances in the development of alginate matrices will continue to contribute to skin regeneration therapy improvements in the future.
